UA121464C2 - Anti-jagged1 antibodies and methods of use - Google Patents

Abstract

The disclosure provides anti-Jagged1 antibodies and methods of using the same.

Description

TECHNICAL FIELD TO WHICH THE INVENTION COVERS

This invention relates to anti-Uaddeay antibodies and methods of their use.

TECHNICAL LEVEL

The Moispy signaling pathway regulates a wide range of cellular functions. Four Moses receptors have been identified in mammals, namely, Moses 1-4, which share basic structural elements, including an extracellular domain, a transmembrane domain, and an intracellular domain. Similarly, the canonical Moispy ligands share a defined structural similarity, but a number of non-canonical ligands have also been identified

Moisy IKorap ei ai., SeiI 137, 216-233 (2009)). The five canonical ligands in mammals are OekKa-

IKe 1, Oeya-yKe Z, Oepa-yKe 4, daddea1 and hadded2. Binding of the Moisp ligand to the extracellular domain of the Moisp receptor triggers a signaling cascade that begins with proteolytic cleavage of extracellular site 52 by alpha-secretase from the ABAM family (disintegrins and metalloproteases). Cleavage at 52 is followed by proteolytic cleavage by gamma-secretase at the intracellular site 53, which leads to the release of the intracellular domain and subsequent events that ultimately activate Moisp-dependent transcription factors such as He51 apa Neu.

Disrupted expression of Moisp and signal transduction are involved in a number of diseases, including cancers. My. And Me 5si. 64, 2746-2762 (2007)). Clearly, there is still a need for agents that have clinical characteristics optimal for the development of therapeutic agents. The invention described herein satisfies this need and provides other advantages.

ESSENCE OF THE INVENTION

The present invention relates to anti-Uaddei1 antibodies and methods of their use.

The authors of this invention unexpectedly found out that the anti-Uaddei1 antibody A1 (see fig. 4 of PCT publication Mo 2014/028446) is cleaved along the heavy chain after heat treatment or freezing-thawing. Poor antibody stability potentially reduces its value as a therapeutic agent. Analysis of the cleavage site revealed no known protease cleavage motifs. Therefore, it was unknown whether changes in the antibody sequence could reduce the observed cleavage. In addition, since the cleavage site is in the NUK

From the heavy chain, even if a change in amino acid(t) would reduce cleavage, it is not known whether the changes could be made without significantly reducing the affinity of the antibody to Daddeia1. The authors of the invention unexpectedly found out that the mutation of the amino acid at position 101 in NMK-NZ reduces cleavage only with a slight loss of affinity.

In some embodiments, an isolated antibody that binds to human daddea1 is provided, wherein the antibody comprises an NME-NZ that contains the amino acid sequence BEO IU MO: 55 or 59, where X is any amino acid except 5. In some embodiments the antibody of the invention contains at least one, at least two, at least three, at least four or five NUKs selected from NME-NI, which contains the amino acid sequence zEO IU MO: 35 or 78; NUV-H2, which contains the amino acid sequence ZEO IU MO: 28 or 36; NMK-11, which contains the amino acid sequence 5ХЕО IЮ MO: 38; NMK-12, which contains the amino acid sequence

ZEO IYUO MO: 39; and NMK-I3, which contains the amino acid sequence 5EO IU MO: 16 or 40. In some embodiments, the antibody contains: (a) NMK-NI, which contains the amino acid sequence BZEO IU MO: 78; NME-NEI, which contains the amino acid sequence zEO IU MO: 36; and

NMV-NZ, which contains an amino acid sequence of 5620 IU MO: 55; or (B) NME-NI, which contains the amino acid sequence zEO IU MO: 78; HME-NaI, which contains the amino acid sequence

ZEO IU MO: 36; and NMA-NZ, which contains the amino acid sequence 5EO IYUO MO: 59; or (c) NMA-

NT, which contains the amino acid sequence zEO IYUO MO: 78; NMAK-NU2, which contains the amino acid sequence BEO IYUO MO: 28; of NMA-NZ, which contains the amino acid sequence 5EO IU MO: 59.

In any of the embodiments described herein, the antibody may comprise (a) HME-I11, which

BO contains the amino acid sequence ZEO IO MO: 38; NMK-12, which contains the amino acid sequence BEO IU MO: 39; ii NMA-1I Z, which contains the amino acid sequence zEO IIU MO: 40; or (B) NMK-11, which contains the amino acid sequence 5EO IU MO: 38; NMK-12, which contains the amino acid sequence 5EO IU MO: 39; NMK-1I 3, which contains the amino acid sequence

ZEO IU MO: 16; or (c) NMK-111, which contains the amino acid sequence "EO IU MO: 38; NME-

I2, which contains the amino acid sequence zZEO IJUO MO: 39; and NME-1I-3, which contains the amino acid sequence ZEO IU MO: 16.

In some embodiments, the isolated antibody that binds to Udaddei 1 comprises: (a)

NMUV-NI, which contains the amino acid sequence of ZEO and MO: 78; NMK-H2, which contains the amino acid sequence zEO IU MO: 36; NMK-NZ, which contains the amino acid sequence 60 ZEO IU MO: 55; NMV-11, which contains the amino acid sequence 5EO IU MO: 38; NME-12, which contains the amino acid sequence ZEO IO MO: 39; of NMK-I3, which contains the amino acid sequence FEO IYUO MO: 40; or (B) NME-NI, which contains the amino acid sequence of ZEO IU

MO: 78; NUV-H2, which contains the amino acid sequence 5ХЕО ИЯ МО: 36; NMK-NZ, which contains the amino acid sequence ZE IU MO: 59; NMK-11, which contains the amino acid sequence

ZEO IO MO: 38; NUV-12, which contains the amino acid sequence ZEO IU MO: 39; ii NMEA-I 3, which contains the amino acid sequence ZEO IU MO: 16; or (c) NME-NI, which contains the amino acid sequence "EO IU MO: 78; NMK-H2, which contains the amino acid sequence zEO IU MO: 28;

NMUV-NZ, which contains the amino acid sequence ZEBEO OO MO: 59; NMK-11, which contains the amino acid sequence 5ХЕО IЮ MO: 38; NMK-12, which contains the amino acid sequence

ZEO IU MO: 39; and NMEA-1I3, which contains the amino acid sequence zZEO IU MO: 16.

In some embodiments, the isolated antibody that binds to daddea! contains a sequence of UN that has at least 95 95 identity to the amino acid sequence of ZE

IU MO: 54, 58 or 62. In some embodiments, an isolated antibody that binds to

U9addea1, contains an MI sequence that has at least 95 95 identity with the amino acid sequence of ZEO IU MO: 10, 26 or 34. In some embodiments, the antibody contains: (a) a UN sequence that has at least 95 95 identity with the amino acid sequence of BEO

IUO MO: 54, and an MI sequence having at least 95 95 identity with the amino acid sequence 5EO IU MO: 34; or (B) a UN sequence that has at least 95 95 identity with the amino acid sequence ZEO IU MO: 58, and an MI sequence that has at least 95 90 identity with the amino acid sequence 5EO IU MO: 10; or (c) a MH sequence that has at least 95 95 identity with the amino acid sequence 5EO IU MO: 62, and the sequence

MI,, which has at least 95 95 identity with the amino acid sequence ZEO IU MO: 26.

In some embodiments, the isolated antibody that binds to human Udhaddeia1 comprises: (a) the sequence MN of 5EO IU MO: 54, where X is any amino acid other than 5, and the sequence

E. with BEO IO MO: 34; or (B) sequence MH with BEO IJOO MO: 58, where X is any amino acid except 5, and sequence MI with ZEO IJOO MO: 10; or (c) the sequence MH with 5EO IU MO: 62, where X is any amino acid except 5, and the sequence MI with 5EO IU MO: 26. In some embodiments of the invention, the antibody comprises the sequence MN with 5EO IO MO: 54 and sequence MI 5EO

IO MO: 34. In some embodiments, the heavy chain comprises an amino acid sequence

Co) ZEO IO MO: 56, and the light chain comprises the amino acid sequence ZEO IUO MO: 53. In some embodiments, the heavy chain comprises the amino acid sequence ZEO IO MO: 57, and the light chain comprises the amino acid sequence zEO IJU MO: 53.

In any of the embodiments described herein, X may be any amino acid except 5 or H. In any of the embodiments described herein, X may be selected from A, O, E, b , I, K, I, M, O, EK, T and M. In any of the variants described in this document, X can be T.

In some embodiments, an isolated antibody that binds to human daddea1 is provided, which includes: (a) NMA-NI, which contains the amino acid sequence zEO IU MO: 78; NME-

H2, which contains the amino acid sequence with "EO IU MO: 36; NMK-NZ, which contains the amino acid sequence zEO IU MO: 37; NMK-11, which contains the amino acid sequence zBEO IO MO: 38;

NMUV-I2, which contains the amino acid sequence ZEO OO MO: 39; and NMK-IZ, which contains the amino acid sequence of ZEO IU MO: 40; or (B) NME-NI, which contains the amino acid sequence "EO IU MO: 78; NMK-H2, which contains the amino acid sequence zEO IU MO: 36;

NMUV-NZ, which contains the amino acid sequence of ZEBEO and MO: 64; NMK-11, which contains the amino acid sequence 5EO IU MO: 38; NMK-12, which contains the amino acid sequence

ZEO IU MO: 39; and NMK-1I 3, which contains the amino acid sequence ZEO IO MO: 16; or (c) NME-

NT, which contains the amino acid sequence zEO IYUO MO: 78; NMAK-H2, which contains the amino acid sequence "EO IU MO: 28; NMK-NZ, which contains the amino acid sequence zEO IU MO: 64;

NMV-I1, which contains the amino acid sequence ZEO OO MO: 38; NMK-I2, which contains the amino acid sequence 5EO IU MO: 39; NMK-1I 3, which contains the amino acid sequence

ZEOIU MO: 16.

In some embodiments, an isolated antibody that binds to human daddea1 is provided, which includes: (a) sequence MH with BEO IO MO: 33 and sequence MI with 5EO IJUO MO: 34; or (B) MH sequence with 5EO IU MO: 65 and MI sequence with ZEO IO MO: 10; or (c) the MN sequence with 5EO IU MO: 66 and the MI sequence with ZEO IU MO: 26. In some embodiments of the invention, the antibody contains the MN sequence with ZEO IU MO: 33 and the MI sequence. with

ZEO IU MO: 34.

In any of the above embodiments described herein, the antibody may be a monoclonal antibody. In some embodiments of the invention, the antibody is a human, humanized, or chimeric antibody. In any of the above embodiments described herein, the antibody may be an antibody fragment.

Any of the above options can be a full-length Ids1 antibody. In some embodiments of the invention, the antibody is an Ids1 antibody without effector functions. In some embodiments, the antibody is an Ids1 antibody that contains mutations M2976 or

M297A. In some embodiments of the invention, the antibody is an Ids1 antibody that contains the M2970 mutation.

In some embodiments, an isolated antibody that binds to daddea 1 is provided, wherein the heavy chain comprises the amino acid sequence 5EO IU MO: 51 and the light chain comprises the amino acid sequence 5EOO IUO MO: 53. In some embodiments, the heavy chain comprises the amino acid sequence 5EO IO MO: 52, and the light chain comprises the amino acid sequence ZE IO MO: 53. In some embodiments, the antibody comprises: (a) a heavy chain comprising the amino acid sequence ZEO IU MO: 69, and a light chain comprising the amino acid sequence 5EO IYU MO: 75; or (5) a heavy chain that contains the amino acid sequence "EO IUO MO: 70, and a light chain that contains the amino acid sequence ZEO IU

MO: 76; or (c) a heavy chain that contains the amino acid sequence ZEO IJU MO: 79, and a light chain that contains the amino acid sequence 5EO IJU MO: 75; or (4) a heavy chain that contains the amino acid sequence ЖЭО IХО MO: 80 and a light chain that contains the amino acid sequence ZEO IЮ MO: 76.

In any of the embodiments described herein, the antibody may be an antagonist

Wadded1-mediated signaling pathway. In some embodiments of the invention, the antibody binds to human and mouse daddei1. In some embodiments of the invention, the antibody binds to human, mouse, rat, and cynomolgus Udhadded1. In some embodiments of the invention, the antibody binds to daddey!, but does not bind to dadded2. In some embodiments of the invention, the antibody binds to daddeia! human, but does not connect to dadded2 human. In some embodiments of the invention, the antibody binds to human and mouse dded1, but does not bind to human or mouse dded2. In some embodiments of the invention, the antibody binds to Udhadded! human, mouse, rat and cynomolgus macaque, but does not bind to

Udaded2 of man, mouse, rat and Javan macaque. In some embodiments of the invention

The antibody binds to Daddei but not to Dadde42 or O111. In some embodiments of the invention, the antibody binds to Daddei! human, but does not bind to human daddea2 or human 0/1. In some embodiments of the invention, the antibody binds to

Uadded1 of human and mouse, but does not bind to Dadded2 of human or mouse or 0/1 of human or mouse. In some embodiments of the invention, the antibody binds to daddey! human, mouse, and cynomolgus macaque, but does not bind to human, mouse, or cynomolgus macaque hadded2 or human, mouse, or cynomolgus macaque OSI 1. In some embodiments of the invention, the antibody binds to daddeia!, but does not bind to dadded2, 0/1 or 01/14. In some embodiments of the invention, the antibody binds to daddeai! human, but does not bind to human Udaddea2, human BT, or human 0/4. In some embodiments of the invention, the antibody binds to human and mouse daddedi, but does not bind to human or mouse dhdadde2, human or mouse 0 AND 1, or human or mouse 01 AND 4. In some embodiments of the invention, the antibody binds to human, mouse, rat, and cynomolgus macaque dadd1, but does not bind to human, mouse, or cynomolgus macaque dadd2, or human, mouse, or cynomolgus 0 1 , or human sbi I 4 , mouse or Javan macaque.

In some embodiments of the invention, the antibody binds to human Dhadde1 with an affinity (Ka) of 2 nM or greater (ie, below 2 nM). In some embodiments, the antibody binds to

Human Uaddedi with an affinity (Ka) of 1.5 nM or greater, or 1 nM or greater, or 0.9 nM or greater, 0.8 nM or greater, or 0.7 nM or greater (ie, below 1.5 nM, below 1 nM, below 0.9

NM, below 0.8 nM or below 0.7 nM). In some embodiments of the invention, the antibody binds dUadded! mice with an affinity (Ka) of 2 nM or greater (ie, below 2 nM). In some embodiments of the invention, the antibody binds murine AddeA1 with an affinity (Ka) of 1.5 nM or greater, or 1 nM or greater, or 0.9 nM or greater, 0.8 nM or greater, 0.7 nM or greater , or 0.6 nM or higher, or 0.5 nM or higher (ie, below 1.5 nM, below 1 nM, below 0.9 nM, below 0.8 nM, below 0.7 nM, below 0.6 nM or below 0.5 nM). In some embodiments, affinity (Ka) is measured using surface plasmon resonance.

In some embodiments of the invention, the antibody binds to human Chaddea with an association constant (Kol) of at least 1.0 En04/Mes, or at least 1.5 Be04/Mes, or at least 2.0E-04/M:»s . In some embodiments of the invention, the antibody binds to human dhadded1 with a dissociation constant (Kb) below 10.0E-04/s or below 9.0E-60 04/s, or below 8.0E-04/s, or below 7 ,0E-04/c5. In some embodiments of the invention, the antibody binds dadded! mice with an association constant (Copl) of at least 1.0E--04/Mes, or at least 1.5E04/Mes, or at least 2.0E04/Mes, or at least

C, 0E04/Mes, or at least 4.0E-04/Mes, or at least 5.0E-04/Mes, or at least 6b.0E04/Mes, or at least 7.0E-04/M»s. In some embodiments of the invention, the antibody binds to mouse Dadde1 with a dissociation constant (Kb) below 10.0E-04/s or below 9.0E-04/s, or below 8.0E-04/s or below 7.0E- 04/s. In some embodiments, association and dissociation constants are measured using surface plasmon resonance.

In some embodiments of the invention, the antibody binds native, folded daddes1, but does not bind denatured daddes1. In some embodiments of the invention, the antibody binds

U9added1! in a solid-phase enzyme-linked immunosorbent assay (EGI5A), but does not bind daddeya! on

Western blot. In some embodiments of the invention, the antibody binds folded Daddea1 in a solid-phase enzyme-linked immunosorbent assay (ELISA) but does not bind denatured Daddea1 on

Western blot. In some embodiments, the antibody binds folded Chaddea1 under physiological conditions, but does not bind denatured Chaddea1.

In some embodiments of the invention, the antibody slows tumor growth in a xenograft mouse model without causing weight loss. In some embodiments of the present invention, the xenograft mouse model is a xenograft model of liver cancer. In some embodiments, tumor growth is reduced by at least 50, at least 60, at least 70, at least 80, or at least 90 95

AMs/day (TO, inhibition of tumor growth in 96).

In some embodiments, the implementation of the use of antibodies to CHUDhadded! reduces lung goblet cell metaplasia in a murine model of airway hyperresponsiveness. In some embodiments, administration of the antibody reduces the number of goblet cells in the lung by at least 30 95 , at least 40 95 , at least 50 95 , at least 60 to , at least 70 95 , at least 80 96 , or at least 90 95 . According to In another aspect, the invention relates to an isolated antibody that competes with any of the above embodiments in specific binding to dhaddea1. In some embodiments, an antibody that competes for binding to human daddea1 with an antibody that contains a heavy chain variable region that contains the sequence 5EO IJOO MO: 33 and a variable region

Ko) light chain, which contains the sequence ZEO IU MO: 34, where the antibody is not antibody A, antibody A-1 or antibody A-2.

In another aspect, the present invention relates to an isolated nucleic acid that encodes an isolated antibody according to the above embodiments. In yet another aspect, the present invention relates to a host cell that contains an isolated nucleic acid that encodes an antibody. In an additional aspect, the present invention relates to a method of producing an antibody, which includes culturing a host cell in such a way that the antibody is produced.

In another aspect, the present invention relates to an immunoconjugate containing an antibody according to any of the above embodiments and a cytotoxic agent.

In another aspect, the present invention relates to a pharmaceutical composition comprising an antibody according to any of the above embodiments and a pharmaceutically acceptable carrier.

In another aspect, an antibody according to any of the above embodiments is provided for use as a medicinal product. In some embodiments, the antibody of any of the above embodiments is provided for use in the treatment of cancer. In some embodiments, the antibody according to any of the above embodiments is provided for use in reducing the growth of cancer cells.

In another aspect, a method of inhibiting the daddea1-mediated signaling pathway is proposed. In one embodiment, a method of inhibiting the daddeai1-mediated signaling pathway of ip migo is proposed. In one embodiment, a method of inhibiting the dhadde1-mediated signaling pathway is proposed.

In another aspect, a method of treating an individual having cancer is provided, comprising administering to the individual an effective amount of an antibody according to any of the above embodiments. In one embodiment, the cancer is selected from the group consisting of: breast cancer, lung cancer, brain cancer, cervical cancer, colon cancer, liver cancer, bile duct cancer, pancreatic cancer, skin cancer, B-cell malignant neoplasms and T-cell malignant neoplasms.

The authors of this invention have found that the effect of anti-UZadded antibodies shifts the differentiation of cells in the respiratory tract from differentiation into secretory cells (including goblet cells) and differentiation into ciliated cells. Signal path

Wadded1! is important for maintaining secretory cell differentiation, as inhibition of the daddea1 signaling pathway prevents goblet cell metaplasia. The authors of this invention also showed that the transformation of Clara cells into cilia is direct and not related to cell division (data not shown). This transdifferentiation of one type of cell into another occurs in the lung of adults and is distinct from the selection of a cellular differentiation pathway that involves the distribution of progenitor cells, for example, after injury or during development. Goblet cell metaplasia, or excess mucus, is a feature of a number of airway diseases, such as asthma, cystic fibrosis, chronic obstructive pulmonary disease (COPD), and Barrett's esophagus. These results of inhibition of the daddea signaling pathway provide a basis for therapeutic applications, including the use of inhibitors

Uadded1 or dadded2 to prevent or reverse goblet cell metaplasia and to treat conditions characterized by excess mucus, such as airway disease (eg, asthma, COPD, cystic fibrosis) and Barrett's esophagus.

In some embodiments, methods of converting a Clara cell into a ciliated cell are provided, which include administering to the individual an antagonistic antibody that binds to Waddedi! human (including, but not limited to, any of the anti-Uddade1 antibodies described herein). In some embodiments, methods of enhancing the conversion of Klara cells into ciliated cells are provided, which include administering to the individual an antagonistic antibody that binds to human ddadd1 (including, but not limited to, any of the anti-dddd1 antibodies described herein) . In some embodiments of the present invention, the Clara cell is present in the respiratory tract of an adult (eg, in the lungs). In some embodiments, transformation occurs without Clara cell division. In some embodiments, the individual has a disease selected from allergies, asthma, autoimmune diseases, diseases associated with goblet cell metaplasia (eg, in the lungs), and diseases associated with excess mucus. In some embodiments of the present invention, the disease is associated with goblet cell metaplasia. In some embodiments of the present invention, the disease is selected from asthma, COPD, cystic fibrosis, and Barrett's esophagus.

In some embodiments, methods of reducing the number of goblet cells are provided, which include administering to the individual an antagonistic antibody that binds to human daddea1 (including, but not limited to, any of the anti-Dadde1 antibodies described in

From this document). In some embodiments, methods of reducing the transformation of Clara cells into goblet cells are provided, which include administering to the individual an antagonistic antibody that binds to human ddadd1 (including, but not limited to, any of the anti-dddd1 antibodies described herein) . In some embodiments, the goblet cell(s) is present in the airways of an adult (eg, the lungs). In some embodiments of the present invention, the individual has a disease selected from allergies, asthma, an autoimmune disease, diseases associated with goblet cell metaplasia (eg, in the lungs), and diseases associated with excess mucus. In some embodiments of the present invention, the disease is associated with goblet cell metaplasia. In some embodiments of the present invention, the disease is selected from asthma, COPD, cystic fibrosis, and Barrett's esophagus.

In some embodiments, methods of reducing goblet cell formation in a subject are provided, which comprise administering to the individual an antagonistic antibody that binds to human Daddea (including, but not limited to, any of the anti-Goblet1 antibodies described herein ). In some embodiments, the formation of goblet cells in the respiratory tract of an adult (for example, in the lungs) is reduced. In some embodiments of the present invention, the individual has a disease selected from allergies, asthma, an autoimmune disease, diseases associated with goblet cell metaplasia (eg, in the lungs), and diseases associated with excess mucus. In some embodiments of the present invention, the disease is associated with goblet cell metaplasia. In some embodiments of the present invention, the disease is selected from asthma, COPD, cystic fibrosis, and Barrett's esophagus.

In some embodiments, methods for reducing the amount of mucus are provided, which include administering to the individual an antagonistic antibody that binds to human Uhadde1 (including, but not limited to, any of the anti-Zadded1 antibodies described herein). In some embodiments, the mucus is mucus in the respiratory tract. In some embodiments, the mucus is present in the respiratory tract of an adult (eg, in the lungs). In some embodiments of the present invention, the individual has a disease selected from allergies, asthma, an autoimmune disease, diseases associated with goblet cell metaplasia (eg, in the lungs), and diseases associated with excess mucus. In some embodiments of the present invention, the disease is associated with goblet cell metaplasia. In some embodiments of the present invention, the disease is selected from asthma, COPD, cystic fibrosis, and Barrett's esophagus.

In some embodiments, methods of increasing the number of ciliated cells are provided, which include administering to the individual an antagonistic antibody that binds to Haddei1! human (including, but not limited to, any of the anti-Added1 antibodies described herein). In some embodiments, methods of enhancing the formation of ciliated cells are provided by administering to an individual an antagonistic antibody that binds to human Uaddea1 (including, but not limited to, any of the anti-Uaddea1 antibodies described herein). In some embodiments, the ciliated cell is present in the respiratory tract of an adult (eg, in the lungs). In some embodiments of the present invention, the individual has a disease selected from allergies, asthma, an autoimmune disease, diseases associated with goblet cell metaplasia (eg, in the lungs), and diseases associated with excess mucus. In some embodiments of the present invention, the disease is associated with goblet cell metaplasia. In some embodiments of the present invention, the disease is selected from asthma, COPD, cystic fibrosis, and esophagitis

Barrett.

In some embodiments, an antibody that binds to Udded1i! human (including, for example, each of the anti-Udded1 antibodies described herein) is provided for use in the treatment of a disease selected from allergy, asthma, autoimmune disease, disease associated with goblet cell metaplasia (e.g., lung) , and diseases associated with excess mucus, comprising administering to an individual with cancer an effective amount of an antibody according to any of the embodiments described herein. In some embodiments of the present invention, the disease is associated with goblet cell metaplasia. In some embodiments of the present invention, the disease is selected from asthma, COPD, cystic fibrosis, and Barrett's esophagus.

In some embodiments, an antibody that binds to Udded1i! human (including, for example, each of the anti-Udded1 antibodies described herein) is provided for use in the treatment of a disease selected from allergy, asthma, autoimmune disease, disease associated with goblet cell metaplasia (e.g., lung) , and

For diseases associated with excess mucus, comprising administering to an individual with cancer an effective amount of an antibody according to any of the embodiments described herein, wherein the antibody that binds to human dhdadde1 enhances cell transformation

Clara in the ciliated cells in the respiratory tract of an adult (for example, in the lungs). In some embodiments of the present invention, the disease is associated with goblet cell metaplasia. In some embodiments of the present invention, the disease is selected from asthma,

COPD, cystic fibrosis and Barrett's esophagus.

In some embodiments, an antibody that binds to Udded1i! human (including, for example, each of the anti-Udded1 antibodies described herein) is provided for use in the treatment of a disease selected from allergy, asthma, autoimmune disease, disease associated with goblet cell metaplasia (e.g., lung) , and diseases associated with excess mucus, comprising administering to an individual with cancer an effective amount of an antibody according to any of the embodiments described herein, wherein the antibody that binds to human daddea1 reduces the number of goblet cells in respiratory tract of an adult (for example, in the lungs). In some embodiments of the present invention, the disease is associated with goblet cell metaplasia. In some embodiments of the present invention, the disease is selected from asthma, COPD, cystic fibrosis, and Barrett's esophagus.

In some embodiments, an antibody that binds to human Dadde1 (including, for example, each of the anti-Dadde1 antibodies described herein) is provided for use in the treatment of a disease selected from allergy, asthma, autoimmune disease, diseases, associated with goblet cell metaplasia (e.g., in the lungs), and diseases associated with excess mucus, comprising administering to an individual with cancer an effective amount of an antibody according to any of the embodiments described herein, wherein the antibody, which contacting Chadday! human, reduces the formation of goblet cells in the respiratory tract of an adult (for example, in the lungs). In some embodiments of the present invention, the disease is associated with goblet cell metaplasia. In some embodiments of the present invention, the disease is selected from asthma,

COPD, cystic fibrosis and Barrett's esophagus.

In some embodiments, an antibody that binds to Udded1i! human (including, for example, each of the anti-Uddaid1 antibodies described herein) proposed for use in the treatment of a disease selected from allergy, asthma, autoimmune disease, disease associated with goblet cell metaplasia (e.g., lung ), and diseases associated with excess mucus, comprising administering to an individual with cancer an effective amount of an antibody according to any of the embodiments described herein, wherein the antibody that binds to Chdhadded! of a person, reduces the amount of mucus in the respiratory tract of an adult (for example, in the lungs). In some embodiments of the present invention, the disease is associated with goblet cell metaplasia. In some embodiments of the present invention, the disease is selected from asthma, COPD, cystic fibrosis, and Barrett's esophagus.

In some embodiments, an antibody that binds to Udded1i! human (including, for example, each of the anti-Udded1 antibodies described herein) is provided for use in the treatment of a disease selected from allergy, asthma, autoimmune disease, disease associated with goblet cell metaplasia (e.g., lung) , and diseases associated with excess mucus, comprising administering to an individual with cancer an effective amount of an antibody according to any of the embodiments described herein, wherein the antibody that binds to human dadded1 increases the number of ciliated cells in respiratory tract of an adult (for example, in the lungs). In some embodiments of the present invention, the disease is associated with goblet cell metaplasia. In some embodiments of the present invention, the disease is selected from asthma, COPD, cystic fibrosis, and Barrett's esophagus.

In some embodiments, an antibody that binds to Udded1i! human (including, for example, each of the anti-Udded1 antibodies described herein) for use in the treatment of a disease selected from allergy, asthma, autoimmune disease, disease associated with goblet cell metaplasia (e.g., lung) , and diseases associated with excess mucus, comprising administering to an individual with cancer an effective amount of an antibody according to any of the embodiments described herein, wherein the antibody that binds to human daddea1 enhances the formation of ciliated cells in respiratory tract of an adult (for example, in the lungs). In some embodiments of the present invention, the disease is associated with goblet cell metaplasia. In some embodiments of the present invention, the disease is selected from asthma, COPD, cystic fibrosis, and Barrett's esophagus.

In another aspect, the proposed methods are: (a) conversion of ciliated cells into Clara cells (for example, where a ciliated cell is located in the respiratory tract of an adult, for example, in the lungs), (B) increasing the amount of mucus (for example, mucus in the respiratory tract), ( c) reducing the number of ciliated cells (for example, ciliated cells of the human respiratory tract), which include the introduction of an individual agonist of the daddea1 signaling pathway.

In some embodiments, a method of treating a disease selected from asthma allergy, autoimmune disease, diseases associated with goblet cell metaplasia (e.g., in the lungs), and diseases associated with excess mucus is provided, comprising administering to a subject with cancer of an effective amount of an antibody that binds to human CHUDade1 (including, for example, each of the antibodies that bind to

Udadded1 of the person described in this document). In some embodiments of the present invention, the disease is associated with goblet cell metaplasia (eg, in the lungs). In some embodiments of the present invention, the disease is selected from asthma, COPD, cystic fibrosis, and Barrett's esophagus.

In any of the embodiments described herein, the anti-Uaddeid1 antibody reduces tumor growth in a xenograft mouse model without causing weight loss.

In any of the options described herein, the anti-Wadded1 antibody can be conjugated to a label. In some embodiments, the tag is a positron emitter. In some embodiments, the positron emitter is 8927. In some embodiments, a method for detecting Chadde4! of a person in a biological sample, which includes providing contact of the biological sample with the antibody described in this document, under conditions that allow binding of the antibody to the natural daddei! of a person, and detection of the formation of a complex between an antibody and natural human Daded1 in a biological sample. In some embodiments of the present invention, the biological sample is selected from breast cancer, lung cancer, brain cancer, cervical cancer, colon cancer, liver cancer, bile duct cancer, pancreatic cancer, skin cancer, B-cell malignancies, and T - cellular malignant neoplasms.

BRIEF DESCRIPTION OF THE FIGURES In fig. 1 shows typical amino acid sequences of human and mouse daddei1 protein.

In fig. 2 shows typical amino acid sequences of human and mouse dadded2 protein.

In fig. ZA-O show the amino acid sequences of the peptides used for screening and selection of the phage library of antibodies. All proteins were expressed as secreted protein in BEM5 cells, and their sequences are indicated from the M-terminus to the C-terminus. (A) Amino acid sequence of the expressed murine dhaddea1-051-ECE1-4 protein (9034-0377).

A short linker sequence (AB 5) is highlighted in bold at the M-terminus (ZEO IYUO MO: 82). Short linker sequence (ES), thrombin cleavage site (SMPKO5) (5EO AND MO: 83), Csi-spacer and 6-histidine tag (6-Niv) are highlighted in bold at the C-terminus. (IN)

Amino acid sequence of the expressed human protein Chdad1-0O5I-ЕСЕ1-4. Only the Uad1 sequence is shown, although the antigen also contained a TEM protease cleavage site and a 6-Niv tag at the C-terminus. (C) Amino acid sequence of the expressed mouse dad2-O51 protein -

ES E1-4 (M27-EZ388). A short linker sequence (Ari ov) is highlighted in bold at the M-terminus (ZBO I MO: 82). The short linker sequence (ECS), thrombin cleavage site (TRS) (ZEO IU MO: 83), C-spacer and 6-

New label. (0) Amino acid sequence of expressed human protein dad2-051-ЕСЕ1-4 (Н2-Е388). Short linker sequence (EES), thrombin cleavage site (I MRKO5) (ZEO IU MO: 83), C-spacer and 6-Nivz tag are highlighted in bold at the C-terminus.

In fig. 4A-1-8-2 shows an alignment of the amino acid sequences for the variable domains of the heavy (Fig. 4A-1 and Fig. 4A-2) and light (Fig. 48-1 and Fig. 4B-2) chains of anti-Chaddea1 (A,

A-1, A-2), anti-Uaddea2 (B, B-1, B-2, B-3) and anti-Uaddea1/2 antibodies (C, C-1, O, 0-1, 0-2 , 0-3, 0-4, 0-5). The amino acid positions of the complementarity-determining regions (COM) are indicated.

In fig. 5A-B show the sequences of the hypervariable regions of the heavy chain (HVC), NO,

H2 and NU, anti-Uadded1 antibodies, described in the examples. Amino acid positions are numbered according to the Kabat numbering system described herein and elsewhere.

In fig. 6 shows the sequences of light chain NMK, 11, 12 and IZ, anti-Uaddeid1 antibodies described in the examples. Amino acid positions are numbered according to the numbering system

The pocket described below.

In fig. 7 shows the sequences of the framework regions of the light and heavy chains of the anti-Chaddes antibodies described in the examples. The numbers in the upper case indicate the positions of the amino acids

Co., Ltd.) by Kabat.

In fig. 8 shows the binding specificity of antibodies obtained after screening. The results of EHIZA analyzes are given, in which the binding specificity of antibodies A and B, identified during screening using human dad1i-O51-ES(E1-4 (Fig. 3B) for antibody A and mouse and human dad2-O51-ESuI1- 4 (Fig. 3C and OB) for antibody B. Black bars - binding to human Daddea1; gray bars - binding to human Xhadde2. C-1 is an antibody that binds to both Daddea1 and Dadde2.

In fig. 9A-B show the inhibition of the Moisp signaling pathway by affinity matured anti-Chaddea antibodies. Assays using co-cultivation were performed as described in example 3. Phage antibodies with a given concentration are indicated on the x-axis. OART at the indicated concentrations served as a positive control for inhibition of the MoiSP signaling pathway; OM5O served as a control medium. The signal was induced with Zaddea1 (dark gray bars) or with addead?2 (light gray bars). Untreated - cultures that were not stimulated with a ligand and not treated with an antibody; Without stimulation - cultures not stimulated by the ligand; adO - control isotype antibody; Stim./without AT - cultures stimulated with a ligand, but not treated with an antibody; SART - gamma-secretase inhibitor or

РМ5О - carrier control for SART.

In fig. T10A-B showed that the combined inhibition of daddeid! and dadded2 leads to rapid weight loss. (A) Mice were dosed twice a week with anti-Uaddei1/2 antibody C-1 (anti-OU1/2; 5-10 trK (mg/kg body weight)), anti-Uaddei1 antibody A-2 (anti-) 1; 5-20 trkK), anti-

Uadded2 antibodies B-3 (anti-9U2; 5-20 trkK), antibodies A-2 and B-3 together (anti-)1852; 5 trK each) or control isotype antibody (20 trK). The total antibody concentration in each dose was adjusted to 20 trk using isotype control antibody where necessary. The change in average body weight (y-axis) was plotted as a percentage of the initial body weight as a function of time (x-axis). (B) Wair/s mice (ten in each group, housed individually) were injected intraperitoneally twice weekly with 30 trK of anti-d0 isotype control antibody or a combination of 15 trK of A-2 antibody plus 15 trK of B-3 antibody for eight days. Food intake was assessed daily by weighing food released and food retained in each cell. Error bars represent standard deviation (n--10).

In fig. 11A-1-8-2 shows the inhibition of the growth of human lung cancer cells by means of an antagonistic anti-Uaddeid1 antibody and mimo. Mice bearing human lung cancer xenografts were injected intraperitoneally (IR) twice a week with 20 trK of anti-90 isotype control antibody (isotype control AT) or anti-Uadd1 antibody A-2 (anti-dazd1), with injections starting after how the average volume of the tumor (measured with a caliper) was about 180 mm3. Tumor volume (y-axis) was then measured for 19 days. Fig. 11A-1 and fig. 11A-2: Mean tumor volume for each group (n-10) was plotted against time (x-axis) using a linear mixed effects model (Fig. 11A-1.). Tumor volumes for each mouse in each group are depicted in the two panels of Fig. 11A-2. Fig. 118-1st fig. 118-2: The total body weight of each mouse was measured and plotted as a percentage change averaged for each group (Fig. 118-1) or for each mouse in each group (Fig. 118-2).

In fig. 12A-B shows the inhibition of the growth of human breast cancer cells by anti-Uaddeai and anti-Uadded2 antagonistic antibodies ip mimolo Mysham SV-17 5SIUO.B9 (with human breast cancer xenografts administered on days 0, 4, 7, 12, 15 , 18, 22, 25, 29, 32, 36, 43, 50 and 57 anti-d40O control isotype antibody (anti-9), control isotype antibody to ragweed antigen (anti-ambrosia), anti-Uaddea1 antibody A-2 in the framework of human Ids1 antibody (anti-)ad1 A-2 (PIDO1)), anti-Uaddei1 antibody A-2 in the framework of mouse Idsg (anti-dad1

A-2 (tidsg2a)) or anti-Dadd2 antibody B-3 in the antibody framework (901 human (anti-Uad2 B-3 (pIdC1)). Tumor volumes (y-axis) for groups (A) or individual animals ( C) were plotted using a linear mixed effects model over time (x-axis).

In fig. 13A-C show heavy chain cleavage of anti-Uaddei1 antibodies. (A) Antibodies

A, A1, and A-2 were analyzed using standard SDS-PAGE electrophoresis methods and protein staining in the absence (-) or presence (G) of OTT reducing agent as indicated. Molecular mass standards (in kDa) are also shown. Panel (B) shows a representative scan of the mass spectrometric (MS) analysis (I C-M5/TOE, reducing conditions) of antibody A-1. The positions of significant fragments (peaks) are annotated and the molecular weights are shown above the peaks. This analysis showed that the cleavage site was located between amino acids 5100 and 5101 in the heavy chain SOCZ, as schematically indicated in the heavy chain amino acid sequence in panel (C) by an arrow indicating the cleavage site.

In fig. 14A-C show the results of the M-terminal peptide sequencing of the cleavage site of the heavy chain of the anti-)addeid1 antibody. Using standard methods of electrophoresis in

Co) DSN-PAGE under reducing conditions and protein staining, full-length and cleaved fragments of preparations of the indicated antibodies (A) were separated and identified. C-terminal (B) and M-terminal (C) cleaved peptide fragments were excised from the gel and sequenced using standard peptide M-terminal sequencing methods to pinpoint the site of cleavage. The sequences highlighted in red in panels (B) and (C) indicate the M-terminus of each of the sequenced peptides, with the sequence in panel (B) indicating the cleavage site and the sequence in panel (C) indicating the M-terminus of the heavy chain.

In fig. 15 shows the effect of changing amino acid 5101 in the heavy chain of anti-Uaddea!1 antibodies on the cleavage of the heavy chain.

In fig. 16A-B show (A) SDS-PAGE analysis of cleavage of anti-addea!1 antibodies incubated at 70 "C; and (c) results (in percent) of heavy chain cleavage observed for each antibody preparation at 70 and at 95,760.

In fig. 17A-B shows (A) analysis by electrophoresis in DSN-PAGE of cleavage of anti-

Uadded1 antibody A1 after various numbers of freeze-thaw cycles, and (B) the percentage of heavy chain cleavage observed under each condition.

In fig. 18A-C show (A) inhibition of Addea1-induced activation of anti-Addea1 by antibodies AT (left columns) and A1(5101T) (right columns) at different concentrations. Panels (B) and (C) show mean values of firefly luciferase activity and mean values of luciferase from Cephalonia, respectively, which were used to calculate the data in (A) as described in Example 10.

In fig. 19 shows immunofluorescence staining of ciliated cells (marked by immunofluorescence detection of alpha-tubulin in the red channel) and Clara cells (marked by immunofluorescence detection of CC10 in the green channel) in the bronchiolar epithelium of mice injected with anti-Added2 antibodies in combination with anti-Added1 antibody A1 or A-1 (5101T) or isotype control, as described in example 11.

In fig. 20A-B show (A) AND ME plots (linear mixed effects) of tumor volume in mice with liver cancer xenografts that received anti-Added1 antibody A1 or A1(51017T) and (B) the treatment groups shown in ( A), as well as dose, tumor volume on the last day of the study (day 44), AOC/day 95 TO (area under the curve per day (inhibition of tumor growth in percent (TOI)) compared to control, where the lower and upper values refer to the minimum and 60 maximum, respectively, value of 95 TO for individual animals in each group), the tumor doubling time per day (TTR 2X) and the number of mice showing a partial response during the experiment (PE).

In fig. 21A-B show (A) and ME plots of mouse body weight versus time for the mice shown in FIG. 20, th (B) treatment groups shown in (A), th dose, 95 change in body weight on the last day of the study (95 W on the last day), maximum change (in 95) in body weight (max. 95 W), day , when the maximum change in body weight occurred (day max. 95 W) and (AOS/day (lower, upper limits)).

In fig. 22A-B show the amino acid sequences of the variable domains (A) of the heavy chain and (B) of the light chain of the anti-Added1 antibody A-1(5101T). The amino acid positions of complementarity determining regions (CDA) are indicated.

In fig. 23A-C show (A) staining with periodic acid - Schiff's reagent of pulmonary airways in mice that received control, anti-Udded!, anti-Udded2 or a combination of anti-d)Added1 and anti-Dadd2 antibodies, (B) determination of the number of goblet cells of cells in the airways of the different treatment groups, and (C) the inflammation index assessed by NaE staining (hematoxylin/eosin).

In fig. 24 shows the binding of (left) anti-Uaddei1 antibody A-2 and (right) anti-

U9added1/2 antibody C-1 with human Chdadded1, mouse Shdadded1, human dadded2, mouse Shdadded2, human 01, mouse 01, human OII4 and mouse OGI 4.

In fig. 25 shows the clearance of the anti-Uaddeid1 antibody A-1-5101T in mice after a single intravenous injection of three different doses of the antibody.

DETAILED DESCRIPTION OF IMPLEMENTATION OPTIONS OF THE INVENTION

I. DEFINITION

For the purposes of this invention, a "human acceptor framework region" is a framework region that contains the amino acid sequence of a light chain variable domain (MI) framework region or a heavy chain variable domain (MH) framework region derived from a human immunoglobulin framework region or a human consensus framework region , defined below. A human acceptor framework region "derived from" a human immunoglobulin framework region or a human consensus framework region may contain the same amino acid sequence, or it may include changes in the amino acid sequence. In some embodiments, the number of amino acid substitutions is 10 or less, 9 or less, 8 or less, 7 or less, 6 or less, 5 or less, 4 or less, 3 or less, or 2 or less. In some embodiments, the human Mi acceptor framework region is identical in sequence to the human immunoglobulin MI framework region or the consensus human framework region sequence. "Affinity" refers to the strength of the sum of the non-covalent interactions between one binding site of a molecule (eg, an antibody) and its binding partner (eg, an antigen). Unless otherwise indicated, the term "binding affinity" as used herein refers to the intrinsic binding affinity, which reflects the interaction in a ratio of 171 between the members of a binding pair (eg, an antibody and an antigen). Affinity of the molecule

X to its partner M can usually be represented by the dissociation constant (Ka).

Affinity can be measured using conventional methods known in the art, including those described herein. Specific illustrative and exemplary embodiments of binding affinity measurements are described below.

An "affinity matured" antibody refers to an antibody with one or more changes in one or more hypervariable regions (HVRs) compared to a parent antibody that does not have such changes, where such changes result in increased affinity of the antibody for the antigen.

The terms "anti-Uaddei antibody" and "antibody that binds dhadde" refer to an antibody that is capable of binding daddea1, daddea2, or daddea!1 and 2 (dadde1/2) with sufficient affinity such that the antibody is useful as a diagnostic and/or therapeutic agent for the targeted effect on the dadday. In one embodiment, the degree of binding of an anti-Uaddey antibody to an unrelated, non-Daddey protein is approximately less than 10 95 of the binding of the antibody to Dadded, as measured, for example, by radioimmunoassay (RIA). In some embodiments, the antibody that binds to daddey has a dissociation constant (Ka) of "1 μM, "100 nM, "10 nM, "1 nM, "0.1 nM, "0.01 nM, or "0.001 nM (eg 108 M or less, eg 108 M to 10-73 M, eg 1079 M to 10-73 M). In some embodiments, the anti-)addei antibody binds to an epitope of Uaddei that is conserved among Chaddea from different species.

The terms "anti-Udded1 antibody" and "antibody that binds to dddd1" refer to an antibody that is able to bind to dddd1! with sufficient affinity that the antibody is useful as a diagnostic and/or therapeutic agent for targeting dadde1.

The term "antibody" is used herein in its broadest sense to encompass various antibody constructs, including, but not limited to, monoclonal antibodies, polyclonal antibodies, polyspecific antibodies (eg, bispecific antibodies), and antibody fragments if they exhibit a desired antigen-binding activity.

As used in this document, the term "asthma" refers to a complex disease characterized by fluctuating and relapsing symptoms, reversible obstruction of the airways (for example, as a result of the action of a bronchodilator) and bronchial hypersensitivity, which may not necessarily be associated with inflammation, which is its basis Examples of asthma include aspirin-sensitive/exacerbated asthma, atopic asthma, severe asthma, mild asthma, moderate to severe asthma, corticosteroid-independent asthma, chronic asthma, corticosteroid-resistant asthma, corticosteroid-resistant asthma, newly diagnosed and untreated asthma due to smoking asthma, asthma not controlled by corticosteroids, and other types of asthma described in . AIPegdu Siip Ittipoi (2010) 126(5):926-938. A "blocking" antibody, or "antagonistic" antibody, is an antibody that essentially inhibits (partially or completely) the biological activity of the antigen to which it binds. "Antibody fragment" refers to a molecule that differs from an intact antibody that contains a portion of an intact antibody that binds to an antigen to which an intact antibody binds. Examples of antibody fragments include, but are not limited to, Em, Bar, Rar',

Eab'-5H, K(ab')", antibodies, linear antibodies, single-chain antibody molecules (for example, 5OEm) and polyspecific antibodies formed from antibody fragments. An "antibody that binds to the same epitope" as a reference antibody refers to an antibody that blocks binding of the reference antibody to its antigen in a competitive assay by 50,905 or more, and conversely, a control antibody blocks binding of the antibody with its antigen in a competitive analysis by 50 95 or more. An example of competitive analysis is given in this description.

The term "chimeric" antibody refers to an antibody in which a portion of the heavy and/or light chain is from one source or biological species, while the remainder of the heavy and/or light chain is from a different source or biological species. The "class" of an antibody refers to the type of constant domain or constant region it carries

From his heavy chain. There are five main classes of antibodies: IA, dO, CHE, dos and DM, and some of them can be further divided into subclasses (isotypes), for example, Ide, Ids2, IdOZ, Ids4, IDA1 and IdA2.

The constant domains of the heavy chain, which correspond to different classes of immunoglobulins, are called a, 6, is, is and M, respectively.

As used herein, the term "cytotoxic agent" refers to a substance that inhibits or interferes with the functioning of cells and/or leads to cell death or destruction. Cytotoxic agents include, but are not limited to, radioactive isotopes (e.g., A2!!, 151, (125, 90 De86, De88. pi), Vigt2, rzg2g, pp, and radioactive isotopes Hz), chemotherapeutic agents, or drugs (e.g. methotrexate, adriamycin, vinca alkaloids (vincristine, vinblastine, etoposide), doxorubicin, melphalan, mitomycin C, chlorambucil, daunorubicin or other intercalating agents), agents that inhibit growth, enzymes and their fragments, such as nucleases, antibiotics, toxins, such as low-molecular-weight toxins or enzymatically active toxins of bacterial, fungal, plant or animal origin, including fragments and/or variants thereof, and various antitumor or anticancer agents disclosed below. "Effector functions" refer to such types of biological activity as may be inherent to Es -regions of antibodies and vary depending on the antibody isotype. Examples of antibody effector functions include C1d binding and complement-dependent cytotoxicity (CCT); interaction with the E-receptor; antibody-dependent cell-mediated cytotoxicity (AICC); phagocytosis; suppression of receptors on the cell surface (for example, B-cell receptors); and B-cell activation. An "effective amount" of an agent, such as a pharmaceutical composition, refers to an amount that is effective in the necessary doses and for the necessary periods of time to achieve the desired therapeutic or prophylactic result.

The term "ERc region" is used herein to refer to the C-terminal region of the immunoglobulin heavy chain, which contains at least a portion of the constant region.

The term includes native sequences of Es regions and variants of Es regions. In one embodiment, the Eso region of the human heavy chain extends from Suz226 or from Pgo230 to the carboxyl end of the heavy chain. However, the C-terminal lysine (I uz447) of the Eso region may or may not be present. Unless otherwise specifically stated in this document, amino acid B residues or E-regions of the constant region are numbered according to the E numbering system),

which is also called the BO index, which is described in the Kabayi ei ai., Zedyepse5 oi Rgoieip5 oi

Ittypoiodis! Ipiegevi, Biy Ea. Ribiis Neanyj 5eguise, Maiiopai! Ipviyshev oi Neay, VeShezaa, MO, 1991. "Framework region" or "EC" refers to the residues of the variable domain, except for the residues of the hypervariable region (HIV). EC of the variable domain, as a rule, consists of four

EB domains: EK1, EK2, EKZ and EK4. Accordingly, the sequences of NUK and EE are usually in the following order in MH (or M): EK1-NI(11)-EN2-H2(I2)-EVNZ-NZI(I 3)-ENAU.

The terms "full-length antibody," "intact antibody," and "whole antibody" are used interchangeably herein to refer to an antibody that has a structure substantially similar to that of a native antibody, or one that has heavy chains that contain an Es region, defined in this description.

The terms "host cell", "host cell line" and "host cell culture" are used interchangeably and refer to cells into which an exogenous nucleic acid has been introduced, including the progeny of such cells. Host cells include "transformants" and "transformed cells", which include the original transformed cell and its progeny regardless of the number of passages. The offspring may not be completely identical in nucleotide content to the parent cell, but may contain mutations. This includes mutant progeny that have a function or biological activity for which the originally transformed cell is screened or selected. A "human antibody" is an antibody that has an amino acid sequence that matches the amino acid sequence of an antibody that is produced by a human or a human cell, or derived from an animal source, that uses the human antibody repertoire or other sequences that encode human antibodies. This definition of a human antibody expressly excludes a humanized antibody that contains antigen-binding residues from an animal antibody. "Human consensus framework region" is a framework region that represents the most frequently occurring amino acid residues in a sample of MI or MN framework region sequences of human immunoglobulins. Usually, the selection of MI or UNN sequences of human immunoglobulins comes from a subset of variable domain sequences. Usually,

Therefore, this subgroup of sequences is the subgroup specified in Kabayi ei ai!., Zedyepsev5 oi Rgoivip5 oi

Ititipo!iodisa! Ipiegevi, Bi Eaiyop, MIN Rybiysayop 91-3242, Ve(Shezaa MO (1991), my!v. 1-3. In one embodiment, the subgroup for MI. is the kappa | subgroup of Kabat et al., see above. In in one embodiment, the subgroup for UN is subgroup III according to Kabat et al., see above. "Humanized antibody" refers to a chimeric antibody that contains amino acid residues from animal NAC and amino acid residues from human EC. In some embodiments, the humanized antibody will contain substantially all of at least one and typically two variable domains wherein all or substantially all of the NMCs (e.g., SOCs) correspond to the NUC of an animal antibody and all or substantially all of the ECs correspond to the ECs of a human antibody Optionally, humanized the antibody may contain at least a region of the antibody constant region that belongs to a human antibody A “humanized form” of an antibody, eg, an animal antibody, refers to an antibody that has undergone a humanization process.

As used herein, the term "hypervariable region" or "HME" refers to each of the regions of the variable domain of an antibody that are hypervariable in sequence ("complementarity determining regions" or "CACs") and/or form structurally determined loops ("hypervariable loops ») and/or contain antigen-contacting residues (“antigenic contacts”). Antibodies usually contain six NMEs: three in MN (NI, H2, NZ) and three in MI. (1, 12, 3). Examples of NUCs herein include: (a) hypervariable loops located between amino acid residues 26-32 (I 1), 50-52 (12), 91-96 (13), 26-32 (NI), 53-55 (H2) and 96-101 (NZ) (Spoinia apa I e5K, 9. Moi. Vioi!. 196: 901-917 (1987); (5) SOC, which are between amino acid residues 24-34 (I 1), 50-56 (I 2), 89-97 (I 3), 31-35 (NI), 50-65 (H2) and 95-102 (NZ) (Kabai yei a!., Zedyepsevs oi Rgoivipv oi Ittipoodisai! Ipiegevi ,

BP Ey. Ribiis Neaii 5egmise, Maiiopai Ipziises oi Neapi, Veijpezaa, MO (1991); (c) antigenic contacts located between amino acid residues 27c-36 (11), 46-55 (12), 89-96 (I 3), 30-35B (NI), 47-58 (H2) and 93-101 (NZ) (MassSaisht ei ai. y). My. Vioi 262: 732-745 (1996)); and (4) combinations (a), (B) and/or (c), which include amino acid residues of NUK 46-56 (12), 47-56 (12), 48-56 (I 2), 49-56 ( 12), 26-35 (NO), 26-356 (NO), 49-65 (Ng), 93-102 (NC) and 94-102 (NC).

Unless otherwise noted, NUK residues and other residues in the variable domain (eg, 60 EE residues) are numbered in this description according to Kabat et al., see above.

An "immunoconjugate" is an antibody conjugated to one or more heterologous molecules, including, but not limited to, a cytotoxic agent. An "individual" or "subject" is a mammal. Mammals include, but are not limited to, domesticated animals (e.g., cows, sheep, cats, dogs, and horses), primates (e.g., humans and non-human primates such as monkeys), rabbits, and rodents (e.g., mice and rats). In some embodiments, the individual is a human. An "isolated" antibody is an antibody that has been separated from a component of its natural environment. In some embodiments, the antibody is purified to greater than 95 95 or 99 95 purity, as determined, for example, electrophoretically (e.g., electrophoresis in DSN-

PAAG, isoelectrofocusing (IEE), capillary electrophoresis) or chromatographically (for example, ion-exchange HPLC or reverse-phase HPLC). For an overview of the methods of assessing the purity of antibodies, see, for example, Riaitap ei ai., U. Spgotaiyodg. In 848: 79-87 (2007). "Isolated" nucleic acid refers to a nucleic acid molecule that has been separated from a component of its natural environment. An isolated nucleic acid includes a nucleic acid molecule that is found in cells that normally contain the nucleic acid molecule, but the nucleic acid molecule is present extrachromosomally or is present on the chromosome in a position that differs from its natural position on the chromosome. "Isolated nucleic acid that encodes an anti-Zaddei antibody" refers to one or more nucleic acid molecules that encode heavy and light chains (or fragments thereof) of an antibody, including such nucleotide molecules in a single vector or separate vectors, and such nucleotide molecules that present in one or more places in the host.

As used herein, the term "monoclonal antibody" refers to an antibody derived from a population of essentially homogeneous antibodies, that is, the individual antibodies that make up the population are identical and/or bind to the same epitope, except for possible antibody variants, for example, those that contain natural mutations or those that arise during the preparation of monoclonal antibodies, with such variants, as a rule, being present in small amounts. Unlike polyclonal antibody preparations, which usually include different antibodies directed against different determinants (epitopes), each monoclonal antibody of a monoclonal antibody preparation is directed against a single antigenic determinant. Such

Thus, the definition "monoclonal" indicates that the property of an antibody is that it is obtained from a substantially homogeneous population of antibodies, and should not be construed as requiring that the antibody be obtained by any particular method. For example, monoclonal antibodies useful in accordance with the present invention can be produced by methods including, but not limited to, hybridoma technology, recombinant DNA methods, phage display methods, and methods that use transgenic animals that contain all immunoglobulin loci. of a person or their part, while such methods and others, which are given as an example of methods of obtaining monoclonal antibodies, are described in this description. A "naked antibody" refers to an antibody that is not conjugated to a heterologous component (eg, a cytotoxic component) or a radioactive label. A "naked" antibody may be present in a pharmaceutical formulation. "Natural antibodies" refer to natural immunoglobulin molecules with different structures.

For example, natural antibodies of class db are heterotetrameric glycoproteins of approximately 150,000 daltons, which consist of two identical light chains and two identical heavy chains, which are connected by a disulfide bond. From the M-terminus to the C-terminus, each heavy chain contains a variable region (VR), also called the heavy chain variable domain, followed by three constant domains (CHN, CH2, and CH3). Similarly, from the M terminus to the C terminus, each light chain contains a variable region (MI), also called a light chain variable domain, followed by a light chain constant domain (CI). The light chain of an antibody can be classified into one of two types, called kappa (k) and lambda (A), based on the amino acid sequence of its constant domain.

The term "package insert" is used to refer to the instructions usually included in the commercial packaging of therapeutic products that contain information about the indications, uses, dosage, administration, combination therapy, contraindications, and/or precautions related to the use of such therapeutic products. "Percent (95) amino acid sequence identity" with respect to a reference polypeptide sequence is defined as the percentage of amino acid residues in the sequence of interest that are identical to amino acid residues in the reference polypeptide sequence after aligning the sequences and introducing breaks, if necessary, to obtain a maximum of 60 percent sequence identity, and excluding any conservative substitutions as part of sequence identity. Alignment for purposes of determining percent identity of amino acid sequences can be achieved in a variety of ways known in the art, for example, using publicly available computer software such as VI AZT, VAG 5T-2, ASOM, or Medaidp (OMA5BTAK) software. Those skilled in the art can determine appropriate parameters for sequence alignment, including any algorithms necessary to achieve maximal alignment over the entire length of the sequences being compared.

However, for the purposes of this invention, the values of 95 amino acid sequence identities are obtained using the AGISM-2 sequence comparison computer program.

A computer program for the comparison of AG ISM-2 sequences was created by Sepepiesi, Ips., and the original text of the program was submitted with user documentation to the US Copyright Office, UmMazpipdiop 0OS, 20559, where it was registered under Mo

Хы510087 of copyright registration in the USA. The AGISM-2 program is freely available from Sepepiyesi, Ips., Zoshii Zap Egapsiso, Saigiogpia, or it can be compiled from the original program text. The ASIOM-2 program should be compiled when used on the ShMIH operating system, including Oidya! MIH Mm4.0О0. All sequence comparison parameters are set by the AGISM-2 program and do not change.

In situations where AGISM-2 is used for amino acid sequence comparisons, the identity of a given amino acid sequence A and a given amino acid sequence B (which can alternatively be rephrased as a given amino acid sequence A that has or contains some 95 identity of amino acid sequence B) is calculated as follows method: 1О0Охparts X/U, where X represents the number of amino acid residues evaluated as identical matches by the program

ATCPSM-2 when aligning sequences A and B with this program, and where U represents the total number of amino acid residues in B. It is clear that if the length of the amino acid sequence

A is not equal to the length of amino acid sequence B, 9o of the identity of amino acid sequence A and sequence B will not be equal to 95 of the identity of amino acid sequence

In sequence A. Unless otherwise noted, all values of 95 amino acid sequence identity used in this specification are obtained as described in

From the previous paragraph using the ASISM-2 computer program.

The term "pharmaceutical composition" refers to a preparation that is in such a form that allows the biological activity of the active ingredient contained therein to manifest itself, and that does not contain additional components that are unacceptably toxic to the subject to whom the composition will be administered. "Pharmaceutically acceptable carrier" refers to an ingredient in a pharmaceutical formulation, other than the active ingredient, that is non-toxic to the subject. A pharmaceutically acceptable carrier includes, but is not limited to, a buffer, excipient, excipient, or preservative.

The term "dadded" or "dad" as used herein refers to any native

Waddei from any vertebrate, including mammals such as primates (eg, humans) and rodents (eg, mice and rats), unless otherwise specified. The term covers "full-sized" unprocessed chaddey as well as any form of chaddey that results from processing in the cell. The term also covers natural variants of Udadide, such as splicing variants or allelic variants. The amino acid sequences of typical human and mouse Uaddea 1 and Dadded2 are shown in Fig. 1 and 2 (5EO IU MO: 1-4), respectively.

As used herein, the term "treatment" (and its grammatical variants "treat" or "affect") refers to clinical intervention in an attempt to alter the natural course of a disease in an individual being treated, and may be performed either prophylactically or in the presence of clinical pathology. Desired effects of the treatment include prevention or recurrence of the disease, alleviation of symptoms, reduction of any direct or indirect pathological effects of the disease, prevention of metastasis, reduction of the rate of development of the disease, improvement or attenuation of the disease state and remission or improvement of the prognosis. In some embodiments of the present invention, antibodies of the present invention are used to delay the development of a disease or disorder.

The term "variable region" or "variable domain" refers to the domain of the heavy or light chain of an antibody that is involved in the binding of an antibody to an antigen. The variable domains of the heavy chain and the light chain (MH and MI, respectively) of a natural antibody usually have similar structures, with each domain containing four conserved framework regions (FC) and three hypervariable regions (HIV). (See, for example, Kipai eyi aI. Kiru Ittipo!odu, 6" ed.,

M.N. Egetap apa So., Rade 91 (2007). One MH- or Mi-domain may be sufficient for adding specificity of binding to the antigen. In addition, antibodies that bind to a specific antigen can be isolated by using the MH- or Mi-domain of the antibody that binds to the antigen to screen a library of complementary MiI/- or MH-domains, respectively. See, for example, Rogpoiapo ei ai., U. Ittipoi. 150: 880-887 (1993); Siakzop ei ai.,

Maitzge 352: 624-628 (1991).

As used herein, the term "vector" refers to a nucleic acid molecule capable of carrying another nucleic acid to which it is linked. The term includes a vector in the form of a self-replicating nucleic acid structure, as well as a vector incorporated into the genome of the host cell into which it is introduced. Some vectors are capable of controlling the expression of nucleic acids with which they are functionally linked. Such vectors are called "expression vectors" in this description.

I. COMPOSITIONS AND METHODS

In one aspect, this invention is based, in part, on the identification of anti-daddea antibodies and their fragments. In some embodiments, antibodies that bind to at least one daddeid are provided. Antibodies according to the invention can be used, for example, to diagnose or treat cancer. Accordingly, the present invention relates to methods, compositions, kits and articles of manufacture related to anti-Zaddei antibodies.

A. Examples of Anti-)addei1 antibodies

In one aspect, the present invention relates to isolated antibodies that bind to daddea1.

In some embodiments of the invention, the antibody binds to dhaddei1! human and mouse. In some embodiments of the invention, the antibody binds to human, mouse and cynomolgus dhadded1. In some embodiments of the invention, the antibody binds to daddea!, but does not bind to dadded2. In some embodiments of the invention, the antibody binds to human daddea1, but does not bind to human dHadded2. In some embodiments of the invention, the antibody binds to human and mouse daddeid1, but does not bind to human or mouse dhdadde2. In some embodiments of the invention, the antibody binds to human, mouse, and cynomolgus Udhaddea1, but does not bind to human, mouse, rat, and cynomolgus dadded2. In some embodiments of the invention, the antibody binds to dadde1, but not to dadde2 or 0111. In some embodiments of the invention, the antibody binds to Chdadde! human, but does not bind to dhadded2 human or 0/1 human. In some embodiments of the invention

The antibody binds to the dadded! human and mouse, but does not bind to human or mouse daddea2 or to human or mouse 0/1. In some embodiments of the invention, the antibody binds to

Human, mouse, and cynomolgus macaque uddaddy, but does not bind to human, mouse, or cynomolgus macaque 01 or 01 human, mouse, or cynomolgus macaque. In some embodiments of the invention, the antibody binds to dadde1 but does not bind to dadde4a2, 01 or 01 | 4. In some embodiments of the invention, the antibody binds to Wadday! of a person, but does not connect

U9added2 person, 0/1 person or 0BI//4 person. In some embodiments of the invention, the antibody binds to human and mouse Udded1, but does not bind to human or mouse dadded2, human or mouse ri, or human or mouse 0/4. In some embodiments of the invention, the antibody binds to human, mouse, or cynomolgus macaque Daddeid1, but does not bind to human, mouse, or cynomolgus macaque Chdaddea2, or to human, mouse, or cynomolgus cynomolgus BI 1, or to human O/I 4 , mouse or Javan macaque.

In some embodiments of the invention, the antibody binds to human dadde1 with an affinity (Ka) of 2 nM or greater (ie, below 2 nM). In some embodiments, the antibody binds to

Human Uadd1i with an affinity (Ka) of 1.5 nM or greater, or 1 nM or greater, or 0.9 nM or greater, 0.8 nM or greater, or 0.7 nM or greater (ie, below 1.5 nM, below 1 nM, below 0.9

NM, below 0.8 nM or below 0.7 nM). In some embodiments of the invention, the antibody binds mouse Daddea!1 with an affinity (Ka) of 2 nM or greater (ie, below 2 nM). In some embodiments of the invention, the antibody binds murine Daddea!1 with an affinity (Ka) of 1.5 nM or greater, or 1 nM or greater, or 0.9 nM or greater, 0.8 nM or greater, 0.7 nM or higher, or

OR 0.6 nM or greater, or 0.5 nM or greater (ie, below 1.5 nM, below 1 nM, below 0.9 nM, below 0.8 nM, below 0.7 nM, below 0.6 nM or below 0.5 nM).

In some embodiments of the invention, the antibody binds native, folded daddes1, but does not bind denatured daddes1. In some embodiments of the invention, the antibody binds

U9addedy1! in the solid-phase enzyme immunoassay (EGIZA), but does not bind Shdaddei1 to

Western blot. In some embodiments of the invention, the antibody binds folded Uadde1 in a solid-phase enzyme-linked immunosorbent assay (ELISA) but does not bind denatured Uadde1 in

Western blot. In some embodiments, the antibody binds folded TSUaddea1 under physiological conditions, but does not bind denatured Daddea1. "Native, collapsed" Wadday1 refers to

Wadded!, which has undergone a protein folding procedure under physiological conditions and remains folded. In some embodiments, Udhadded1 remains in a folded state in solution.

In some embodiments, the present invention relates to an anti-Zaddea1 antibody that contains at least one, two, three, four, five, or six NMEAs selected from: (a) NMEA-NI, which contains the amino acid sequence 5EO IU MO: 35 or 78; (B) HME-H2, which contains the amino acid sequence FEO IU MO: 28 or 36; (c) NMA-NZ, which contains the amino acid sequence of ES

IOJUO MO: 55 or 59, where X is any amino acid except 5; (4) NMEA-11, which contains the amino acid sequence ES 10 MO: 38; (c) NMK-12, which contains the amino acid sequence "EO IU MO: 39; (I) NMK-1I 3, which contains the amino acid sequence zEO IJ MO: 16 or 40. In some embodiments, the present invention relates to an anti-Uaddei1 antibody that contains at least one, two, three, four, five or six NUC , selected from: (a) NME-NI, which contains the amino acid sequence ZEO IO MO: 35 or 78; (B) NMUV-H2, which contains the amino acid sequence ZE OO MO: 36; (c) NMK-NZ, which contains the amino acid sequence ZEO IU MO: 55, where X is any amino acid except 5; (4) NMK-11, which contains the amino acid sequence ES 10 MO: 38; (c) NMK-12, which contains the amino acid sequence "EO IU MO: 39; ii (I) NMK-1I 3, which contains the amino acid sequence 5EO IIU MO: 40. In some embodiments, the present invention relates to an anti-Zaddei1 antibody that contains at least one, two, three, four, five or six NUCs selected with: (a) NME-NI, which contains the amino acid sequence 5EO IU MO: 35 or 78; (B) HME-H2, which contains the amino acid sequence "EO IYUO MO: 28; (c) NMEA-NZ, which contains the amino acid sequence 5EO IU MO: 59, where X is any amino acid except 5; (4) NMA-I1, which contains the amino acid sequence BEO IU MO: 38; (c) NMK-12, which contains the amino acid sequence BEO IU MO: 39; and () NMK-1I3, which contains the amino acid sequence BHEO IU MO: 16. In some embodiments, the present invention relates to anti-Uaddeid1! an antibody that contains at least one, two, three, four, five or six NMC selected from: (a) NME-NI, which contains the amino acid sequence FEO IU MO: 35 or 78; (B) HME-H2, which contains the amino acid sequence of XE

IO MO: 36; (c) NUV-NZ, which contains the amino acid sequence zZEO IJU MO: 59, where X is any amino acid except 5; (4) NMK-11, which contains the amino acid sequence 5EO IU MO: 38; (is)

NMUV-12, which contains the amino acid sequence ZEO IO MO: 39; and () NMK-13, which contains

Ko) the amino acid sequence zHEO IU MO: 16. In some embodiments, X is any amino acid except 5. In some embodiments, X is any amino acid other than 5 or H. In some embodiments, X is selected from A ,O, E, b, I.K, I, M O.K, TIM. In some embodiments, X is T.

In some embodiments, the present invention relates to an anti-Zaddea1 antibody that contains at least one, two, three, four, five, or six NUCs selected from: (a) HME-NI, which contains the amino acid sequence 5EO IU MO: 35 or 78; (B) NME-H2, which contains the amino acid sequence "EC IYUO MO: 36; (c) NMEA-NZ, which contains the amino acid sequence 5EO IU MO: 37; (a) NMV-11, which contains the amino acid sequence zHEO IU MO: 38; (c) NUV-12, which contains the amino acid sequence ZE IO MO: 39; and () NMK-IZ, which contains the amino acid sequence BHEO IO MO: 40. In some embodiments, the present invention relates to anti-

Uaddedi antibody, which contains at least one, two, three, four, five or six NUK selected from: (a) HME-NI, which contains the amino acid sequence ZEO IJUO MO: 35 or 78; (B)

NMUV-H2, which contains the amino acid sequence ZEO IO MO: 28; (c) NMEK-NZ, which contains the amino acid sequence ES 10 MO: 64; (4) NMV-I1, which contains the amino acid sequence BEO IU MO: 38; (c) NMK-12, which contains the amino acid sequence BEO IU MO: 39; and () NMK-1I3, which contains the amino acid sequence BHEO IU MO: 16. In some embodiments, the present invention relates to anti-Uaddeid1! an antibody that contains at least one, two, three, four, five or six NMEK selected from: (a) NME-NI, which contains the amino acid sequence FEO IU MO: 35 or 78; (B) HME-H2, which contains the amino acid sequence of XE

BO IO MO: 36; (c) NUV-NZ, which contains the amino acid sequence ZEO IYUO MO: 64; (4) NME-1 1, which contains the amino acid sequence ES IYUO MO: 38; (c) NMK-12, which contains the amino acid sequence "EO IU MO: 39; (I) NMK-1I 3, which contains the amino acid sequence 5EO IYU MO: 16.

In one aspect, the present invention relates to an antibody that contains at least one, at least two, or all three sequences of MH NM selected from: (a) HME-NI, which contains the amino acid sequence 5EO IJU MO: 35 or 78; (B) NME-H2, which contains the amino acid sequence zEO IU MO: 28 or 36; and (c) NMA-NZ, which contains the amino acid sequence of BE

IO MO: 55 or 59, where X is any amino acid except 5. In one embodiment, the antibody contains an HME-NZ that contains the amino acid sequence "EO IU MO: 55 or 59, where X is any amino acid, except for 5. In another embodiment, the antibody contains NMK-

НЗ, which contains the amino acid sequence ZEO IU MO: 55 or 59, where X represents any amino acid except 5, and HME-1I 3, which contains the amino acid sequence ZBEO IU MO: 16 or 40.

In another embodiment of the invention, the antibody includes NMK-NZ, which contains the amino acid sequence FEO IJU MO: 55 or 59, where X represents any amino acid except 5, NMRA-Y Z, which contains the amino acid sequence ZEO I MO: 16 or 40, and NMK-H2, which contains the amino acid sequence ZEO IJU MO: 28 or 36. In an additional embodiment, the antibody includes: (a) NME-NI, which contains the amino acid sequence ZEO IJU MO: 35 or 78; (c) NMA-

H2, which contains an amino acid sequence of 560 IU MO: 28 or 36; and (c) an NMA-NZ that contains the amino acid sequence ZEO IU MO: 55 or 59, where X is any amino acid other than 5. In some embodiments, X is any amino acid other than 5. In some embodiments, implementation X is any amino acid except 5 or H. In some embodiments of the invention, X is selected from A, O, E, b, I, K, I, M, O, KE, T, and M. In some embodiments, X is himself T.

In one aspect, the present invention relates to an antibody that contains at least one, at least two, or all three sequences of MH NMC selected from: (a) NME-NI, which contains the amino acid sequence 5EO IJU MO: 35 or 78; (B) HME-H2, which contains the amino acid sequence of ЭО ИЯ МО: 36; and (c) an NMEA-NZ that contains the amino acid sequence 5EO IJU MO: 55, where X is any amino acid other than 5. In one embodiment, the antibody comprises an NMEA-NZ that contains the amino acid sequence ZEO IJU MO: 55, where X is any amino acid except 5. In another embodiment, the antibody contains HME-NZ, which contains the amino acid sequence zEO IU MO: 55, where X is any amino acid except 5, and NMKA-Y Z, which contains amino acid sequence ZE IO MO: 40. In another embodiment, the antibody contains NMK-NZ, which contains the amino acid sequence зЭО IO MO: 55, where X is any amino acid except 5, HME-I-3, which contains the amino acid sequence sequence of ZEO IU

MO: 40, and NMA-Na2, which contains the amino acid sequence zEO IJU MO: 36. in another embodiment, the antibody contains: (a) NMA-NI, which contains the amino acid sequence 5EO IJU MO: 35 or 78; (B) NMEA-Na, which contains the amino acid sequence ХЕО ИЯ МО: 36; and (c) an NMA-NZ comprising the amino acid sequence zZEO IJUO MO: 55, where X is any amino acid except 5. In some embodiments, X is any amino acid other than 5. In some embodiments, X is is any amino acid except 5 or H. In some embodiments of the invention, X is selected from A, O, E, b, I, K, I, M, O, KE, T, and M. In some embodiments, X is T In an additional embodiment, the antibody includes: (a) HME-NI, which contains the amino acid sequence 5EO IU MO: 35 or 78; (B) HME-H2, which contains the amino acid sequence of ЭО ИЯ МО: 36; and (c) NUV-NZ, which contains the amino acid sequence 52E0 IU MO: 37.

In one aspect, the present invention relates to an antibody that contains at least one, at least two, or all three sequences of MAN NM selected from: (a) NMK-NI, which contains the amino acid sequence 5EO IJU MO: 35 or 78; (B) HME-H2, which contains the amino acid sequence 5EO IU MO: 28; and (c) NMA-NZ, which contains the amino acid sequence 52E0 IJU MO: 59, where X represents any amino acid except 5. In one embodiment, the antibody includes NUV-NZ, which contains the amino acid sequence XEO IJUO MO: 59, where X is any amino acid except 5. In another embodiment, the antibody includes NMK-NZ, which contains the amino acid sequence 5EO IU MO: 59, where X is any amino acid except 5, and NMEA-I-3, which contains the amino acid sequence "EO IU MO: 16. In another embodiment, the antibody includes NMAK-NZ, which contains the amino acid sequence zBEO IU MO: 59, where X represents any amino acid except 5, HMP-I3, which contains amino acid sequence BZEO IU MO: 16, and NMA-Na2, which contains the amino acid sequence 5EO IU MO: 28.

In another embodiment, the antibody includes: (a) NME-NI, which contains the amino acid sequence FEO IU MO: 35 or 78; (B) HME-H2, which contains the amino acid sequence of HEO

BO IO MO: 28; and (c) an NMA-NZ comprising the amino acid sequence ZEO IU MO: 59, where X is any amino acid except 5. In some embodiments, X is any amino acid other than 5. In some embodiments, X is is any amino acid except 5 or H. In some embodiments of the invention, X is selected from A, O, E, b, I, K, 1, M O.K, Ti M. In some embodiments, X is T. In an additional in an embodiment, the antibody includes: (a) NME-NI, which contains the amino acid sequence ZEO IU MO: 35 or 78; (c) NMK-

H2, which contains the amino acid sequence ZEO IO MO: 28; and (c) NMK-NZ, which contains the amino acid sequence ZEO IU MO: 64.

In one aspect, the present invention relates to an antibody that contains at least one, at least two, or all three sequences of MAN NM selected from: (a) NMK-NI, which contains the 60 amino acid sequence 5EO IU MO: 35 or 78; (B) HME-H2, which contains the amino acid sequence of ЭО ИЯ МО: 36; and (c) NMA-NZ, which contains the amino acid sequence XEO IJU MO: 59, where X is any amino acid except 5. In one embodiment, the antibody includes NMC-NZ, which contains the amino acid sequence XEO IJU MO: 59, where X is any amino acid except 5. In another embodiment, the antibody includes NMK-NZ, which contains the amino acid sequence 5EO IU MO: 59, where X is any amino acid except 5, and NMEA-I-3, which contains the amino acid sequence "EO IU MO: 16. In another embodiment, the antibody includes NMAK-NZ, which contains the amino acid sequence zBEO IU MO: 59, where X represents any amino acid except 5, HMP-I3, which contains amino acid sequence BZEO IU MO: 16, and NMA-Na2, which contains the amino acid sequence 5EO IU MO: 36.

In another embodiment, the antibody includes: (a) NMK-NI, which contains the amino acid sequence FEO IU MO: 35 or 78; (B) HME-H2, which contains the amino acid sequence of XE

IO MO: 36; and (c) an NMA-NZ comprising the amino acid sequence ZEO IU MO: 59, where X is any amino acid except 5. In some embodiments, X is any amino acid other than 5. In some embodiments, X is is any amino acid except 5 or H. In some embodiments of the invention, X is selected from A, O, E, C, K.I, M O.K, T M. In some embodiments, X is T. In another embodiment the antibody includes: (a) NME-NI, which contains the amino acid sequence ZEO IU MO: 35 or 78; (B) NME-H2, which contains the amino acid sequence 5ES IYUO MO: 36; and (c) NME-NZ, which contains the amino acid sequence ZEO IU MO: 64.

In another aspect, the present invention relates to an antibody that contains at least one, at least two, or all three MI NMK sequences selected from: (a) NMEK-I1, which contains an amino acid sequence with ZEO IU MO: 38; (B) NMUV-I2, which contains the amino acid sequence of ХЕО ИХО МО: 39; and (c) NMA-IZ, which contains the amino acid sequence zEO IU MO: 16 or 40. In one embodiment, the antibody contains (a) NMK-11, which contains the amino acid sequence ZEO IU MO: 38; (p) NUV-12, which contains the amino acid sequence ZEO IU MO: 39; and (c) HMA-I3, which contains the amino acid sequence 5EO IU MO: 16 or 40. In one embodiment, the antibody contains (a) NMEK-11, which contains the amino acid sequence FEO

IO MO: 38; (b) NUV-12, which contains the amino acid sequence zZEO IU MO: 359; and (c) NME-1I 3, which contains the amino acid sequence ZEO IJU MO: 16. In one embodiment, the antibody includes: (a) NMK-11, which contains the amino acid sequence zEO IJU MO: 38; (B) NUV-12, which contains the amino acid sequence 5EO IO MO: 39; and (c) NMK-I3, which contains the amino acid sequence ZEO IU MO: 40.

In another aspect, the antibody of the present invention includes: (a) a MH domain that contains at least one, at least two, or all three MH NUK sequences selected from (i) HME-NI, which contains the amino acid sequence 5EO I MO: 35 or 78 , (ii) NMK-H2, which contains the amino acid sequence ZEO IU MO: 28 or 36, and (ii) NME-NZ, which contains the amino acid sequence selected from BEO IO MO: 55 or 59, where X represents any amino acid, except 5; and (5) a Mi domain that contains at least one, at least two, or all three Mi sequences.

NMEs selected from (i) NMA-11, which contains the amino acid sequence ZEO IYU MO: 38, (ii) NMK-12, which contains the amino acid sequence 5EO IYUO MO: 39, and (c) NMK-1I 3, which contains the amino acid sequence sequence zEO IO MO: 16 or 40. In another aspect, the antibody of the present invention comprises: (a)

MH-domain, which contains at least one, at least two or all three sequences of MH NMC, selected from (i) NME-NI, which contains the amino acid sequence ZEO IU MO: 35 or 78, (its) NMA-

H2, which contains the amino acid sequence ZE IO MO: 36, and (iii) NMK-NZ, which contains the amino acid sequence selected from ZEO IJO MO: 55, where X is any amino acid except 5; and (5) a Mi domain that contains at least one, at least two, or all three Mi sequences.

NMEs selected from (i) NMA-11, which contains the amino acid sequence from BZEO IU MO: 38, (ii) NME-12, which contains the amino acid sequence xEO IU MO: 39, and (c) NMA-I-3, which contains the amino acid sequence BEO IU MO: 40. In another aspect, the antibody of the present invention includes: (a) an MH domain that contains at least one, at least two, or all three MH NUK sequences selected from (i) HME-NI, which contains amino acid sequence of ZEO IU MO: 35 or 78, (its) NMA-

H2, which contains the amino acid sequence ZEO IO MO: 28, and (ii) NMK-NZ, which contains the amino acid sequence selected from ZEO IJO MO: 59, where X is any amino acid except 5; and (5) a Mi domain that contains at least one, at least two, or all three Mi sequences.

NMEs selected from (i) NMA-11, which contains the amino acid sequence ZEO IYU MO: 38, (ii) NMK-12, which contains the amino acid sequence 5EO IYUO MO: 39, and (c) NMK-1I 3, which contains the amino acid sequence sequence BEO IU MO: 16. In another aspect, the antibody of the present invention includes: (a) an MN domain that contains at least one, at least two, or all three MN NUK sequences selected from (i) HME-NI, which contains an amino acid sequence 5xEO IU MO: 35 or 78, (ii) NMAK-60 H2, which contains the amino acid sequence ZE IU MO: 36, and (ii) NMK-NZ, which contains an amino acid sequence selected from ZEO IUO MO: 59, where X is any amino acid except 5; and (5) a Mi domain that contains at least one, at least two, or all three Mi sequences.

NMEs selected from (i) NMA-11, which contains the amino acid sequence ZEO IYU MO: 38, (ii) NMK-12, which contains the amino acid sequence 5EO IYUO MO: 39, and (c) NMK-1I 3, which contains the amino acid sequence sequence 5EO IU MO: 16. In some embodiments, X is any amino acid other than 5. In some embodiments, X is any amino acid other than 5 or H. In some embodiments, X is selected from A, O, E, b, I.K, M O.K, Ti M.

In another aspect, the antibody of the present invention includes: (a) an MH domain that contains (i) NMEA-

NO, which contains the amino acid sequence ZEO IU MO: 35 or 78, (ii) NMA-H2, which contains the amino acid sequence ZEO IU MO: 28 or 36, and (ii) HME-NZ, which contains the amino acid sequence selected from BEO IU MO: 55 or 59, where X is any amino acid except 5; and (5) M-domain, which contains (i) NMA-11, which contains the amino acid sequence 5EO IJU MO: 38, (its) NMA-12, which contains the amino acid sequence 5EO IJU MO: 39, and (c) NMAK- I3Z, which contains the amino acid sequence ZEO IU MO: 16 or 40. in another aspect, the antibody of the present invention includes: (a) MH domain, which contains () NMMK-NI, which contains the amino acid sequence PEO IU MO: 35 or 78, (ii) NUMV-H2, which contains the amino acid sequence of ZEO

IO MO: 36, and (iii) NMA-NZ, which contains an amino acid sequence selected from ZEO IO MO: 55, where X is any amino acid except 5; and (B) Mi-domain, which contains (i) NMA-11, which contains the amino acid sequence ES OO MO: 38, (i) NMK-I2, which contains the amino acid sequence ХЕО IХО MO: 39, and (c) NMA- IZ, which contains the amino acid sequence zZEO IJU MO: 40. In another aspect, the antibody of the present invention includes: (a) MH-domain, which contains (i) HMA-

NO, which contains the amino acid sequence ZEO IU MO: 35 or 78, (ii) NMA-H2, which contains the amino acid sequence ES IU MO: 28, and (ii) NMK-NZ, which contains the amino acid sequence selected from ZEO IU MO: 59, where X is any amino acid except 5; and (p) the MI domain, which contains (i) NMA-11, which contains the amino acid sequence zEO IU MO: 38, (ii) NMEK-12, which contains the amino acid sequence BEO IO MO: 39, and (c) NME :- IS, which contains the amino acid sequence BEO IU MO: 16. In another aspect, the antibody of the present invention includes: (a) MH domain, which contains (i) HME-NI, which contains the amino acid sequence 5EO IU MO: 35 or 78 , (her) NMBA-H2, which contains the amino acid sequence 5EO IU MO: 36, and (ii) NMA-NH, which contains

Co) an amino acid sequence selected from ZEO IU MO: 59, where X is any amino acid except 5; and (5) M-domain, which contains (i) NMA-11, which contains the amino acid sequence 5EO IU MO: 38, (its) NMA-12, which contains the amino acid sequence 5EO IU MO: 39, and (c) NMK- I3Z, which contains the amino acid sequence zXEO IU MO: 16. In some embodiments, X is any amino acid other than 5. In some embodiments, X is any amino acid other than 5 or H. In some embodiments, X is selected from A ,O,E, s, I.K, I, M, OO, BK, Ti M.

In another aspect, the antibody of the present invention includes: (a) an MH domain that contains at least one, at least two, or all three MH NUK sequences selected from (i) HMA-NI, which contains the amino acid sequence ZESO IU MO: 35 or 78 , (ii) NUV-H2, which contains the amino acid sequence ES IO MO: 36, and (ii) NMK-NZ, which contains the amino acid sequence selected from 5EO IYUO MO: 37; and (B) an Mi domain that contains at least one, at least two, or all three MI sequences of NMC selected from (i) NMC-11, which contains the amino acid sequence 5EO 10 MO: 38, (i) NMC-I2, which contains amino acid sequence ХЕО ІХО MO: 39, and (c) NMA-IZ, which contains the amino acid sequence zZEO ІХ MO: 40. In another aspect, the antibody of the present invention includes: (a) MH domain, which contains at least one, at least two or all three sequences of MH NUK selected from (i) NME-NI, which contains the amino acid sequence 5EO I MO: 35 or 78, (ii) NMK-H2, which contains the amino acid sequence ES IO MO: 28, and (ii) NMA- NZ, which contains an amino acid sequence selected from 5EO IYUO MO: 64; and (B) a Mi domain that contains at least one, at least two, or all three MI NM sequences selected from (|) NMPE-11, which contains the amino acid sequence 5EO 10 MO: 38, (i) NMK-12, which contains the amino acid sequence of ХЕО ИЮО MO: 39, and (c) NMA-IZ, which contains the amino acid sequence зЗЕО ЙЮ МО: 16.

In another aspect, the antibody of the present invention includes: (a) a MH domain that contains at least one, at least two, or all three MH NUK sequences selected from (i) HME-NI, which contains the amino acid sequence 5EO I MO: 35 or 78 , (ii) NMK-H2, which contains the amino acid sequence ES IO MO: 36, and (ii) NMK-NZ, which contains the amino acid sequence selected from 5EO IYUO MO: 64; and (B) an Mi domain that contains at least one, at least two, or all three MI NM sequences selected from (|) NMPE-11, which contains the amino acid sequence 5EO 10 MO: 38, (i) NMK-I2, which contains 60 amino acid sequence of ХЕО ИХО МО: 39, th (c) NMA-IZ, which contains the amino acid sequence 5260 ИЮ МО:

16. In another aspect, the antibody of the present invention includes: (a) a MH domain that contains (ii) HMA-

NO, which contains the amino acid sequence ZEO IYU MO: 35 or 78, (iii) NMA-H2, which contains the amino acid sequence ES IYUO MO: 36, and (ii) NMK-NZ, which contains the amino acid sequence selected from BEO IYUO MO: 37; and (B) the Mi domain, which contains (i) NMK-1I1, which contains the amino acid sequence 5EO 10 MO: 38, (i) NMK-I2, which contains the amino acid sequence ХЕО ИХО MO: 39, and (c) NMA- IZ, which contains the amino acid sequence zZEO IJU MO: 40. In another aspect, the antibody of the present invention includes: (a) MH-domain, which contains (i) HMA-

NO, which contains the amino acid sequence ZEO IU MO: 35 or 78, (ii) NMA-H2, which contains the amino acid sequence ES IU MO: 28, and (ii) NMK-NZ, which contains the amino acid sequence selected from BEO IJU MO: 64; and (B) Mi domain, which contains (i) NMK-1I1, which contains the amino acid sequence 5EO 10 MO: 38, (i) NMK-I2, which contains the amino acid sequence ХЕО ИХО MO: 39, and (c) NMA- IZ, which contains the amino acid sequence zZEO IJU MO: 16. In another aspect, the antibody of the present invention includes: (a) an MN-domain, which contains (ii) NMA-

NO, which contains the amino acid sequence 5EO IU MO: 35 or 78, (ii) NUV-H2, which contains the amino acid sequence ES IU MO: 36, and (ii) NMK-NZ, which contains the amino acid sequence selected from BEO IYUO MO: 64; and (B) Mi domain, which contains (i) NMK-1I1, which contains the amino acid sequence 5EO 10 MO: 38, (i) NMK-12, which contains the amino acid sequence ХЕО ИХО MO: 39, and (c) NMA- IZ, which contains the amino acid sequence zZEO IU MO: 16.

In some embodiments, the anti-Uaddei1 antibody comprises: (a) an MN domain that contains (His)

HMV-NI, which contains the amino acid sequence 5EO IJU MO: 35 or 78, (ii) HMA-H2, which contains the amino acid sequence 5EO IJU MO: 71, where X1 is selected from P and C, X2 is selected from M, and x3 is selected from T and 5, and (iii) NMAK-NZ, which contains an amino acid sequence selected from BEO IU MO: 72, where X1 is any amino acid except 5, and X2 is MM or I; and (B) Mi -domain, which contains (i) NMA-

HER, which contains the amino acid sequence ZEO IU MO: 38, (i) NMK-12, which contains the amino acid sequence with 5EBO I MO: 39, and (c) NMK-IZ, which contains the amino acid sequence zEO IU MO: 74, where X1 is 5 or Y, X2 is P or A, and X3Z is P or T. In some embodiments, X1! in ZEO IU MO: 72 is any amino acid except 5 or H. In some embodiments of the present invention, X1 in 5EO IU MO: 72 is selected from A, O, EE, C, I, K, I, M, O, B ,

Ko) T and M. In some variants of implementation of X1 in 5EO IU MO: 72 there is T.

In one embodiment, anti-Wadded! the antibody contains an NMC, as in any of the above embodiments, and additionally contains a human acceptor framework region, for example, a human immunoglobulin framework region or a human consensus framework region. In another embodiment, the anti-dUdaddea1 antibody comprises an NMUE, as in any of the above embodiments, and further comprises a MH that contains at least one, two, three, or four ECs selected from EC1 that contains an amino acid sequence of BEO IYUO MO: 47; EK2, which contains the amino acid sequence of ZEO and MO: 48; IVF, which contains the amino acid sequence ZEO IYUO MO: 49; and EK4, which contains the amino acid sequence 5EO IU MO: 50. In another embodiment, the anti-Uaddeid1 antibody includes an NMC, as in any of the above embodiments, and additionally contains an Mi that contains at least one, two, three , or four EE selected from the EC, which contains the amino acid sequence BEO IYUO MO: 43; EK2, which contains the amino acid sequence ZEO IYUO MO: 44; IVF, which contains the amino acid sequence ZEO IYUO MO: 45; and EK4, which contains the amino acid sequence ZEO IU MO: 46.

In another aspect, the anti-Waddedi! the antibody includes a heavy chain variable domain (HCH) sequence that has at least 90 95, 91 95, 92 9o, 93 90, 94 95, 95 90, 96 95, 97 95, 98 uo, 99 95, or 100 95 sequence identity with by the amino acid sequence 5EO IU MO: 54, 58, or 62, where X is any amino acid except 5. In some such embodiments, the MH sequence comprises a NMAC-NZ with 5EBEO IU MO: 55 or 59, where X is any amino acid other than 5. In some embodiments, the MH contains one, two or three NMEs selected from: (a) NME-NI, which contains the amino acid sequence ZEO IJUO MO: 35 or 78, (B)

NMUV-H2, which contains the amino acid sequence 5EO OO MO: 55 or 59, where X is any amino acid other than 5, and (c) HME-NZ, which contains the amino acid sequence zXEO IU MO: 37 or 64. In some embodiments embodiment X is any amino acid other than 5. In some embodiments, X is any amino acid other than 5 or H. In some embodiments, X is selected from A, OXXO, E, b, I, DO, Y, , M, O, EC, T, and M. In some embodiments, X is T. In another aspect, the anti-Added1 antibody comprises a heavy chain variable domain (HCH) sequence having at least 905, 94 90, 95 905, 96 905, 97 905, 98 95, 99 95, or 100 95 sequence identity with the amino acid sequence of ZEO 60 IO MO: 33, 65, or 66. In some such embodiments, the MN sequence comprises a NMK -NZ with

ZEO IUO MO: 37 or 64. In some embodiments, the MH contains one, two or three NMCs selected from: (a) NME-NI, which contains the amino acid sequence ZEO IUO MO: 35 or 78, (B)

NMUV-H2, which contains the amino acid sequence ZEO IJU MO: 28 or 36, and (c) NMA-NZ, which contains the amino acid sequence 5EO IJU MO: 37 or 64. In some embodiments, the UN sequence having at least 90 95, 91 95, 92 95, 93 905, 94 95, 95 90, 96 905, 97 95, 98 90 or 99 95 identity, contains substitutions (eg, conservative substitutions), insertions or deletions relative to the reference sequence, but anti-)addei! an antibody containing this sequence retains the ability to bind at least one dadded1. In some embodiments, the substitutions, insertions, or deletions are in regions outside the NMC (ie, in the EC). In some embodiments, the anti-Uddaid1 antibody comprises a heavy chain variable domain (HCH) sequence having at least 90 965, 91 95, 92 95, 93 90, 94 905, 95 905, 96 95, 97 95, 98 95, 99 95 or 100

Fo sequence identity with the amino acid sequence 5EO IUO MO: 33. In some such embodiments, the MN sequence comprises a NMK-NZ with 5EO IU MO: 37. In some embodiments of the present invention, the MN includes one, two, or three NUCs selected from: ( a) NME-NI, which contains the amino acid sequence ZEO 10 MO: 35 or 78, (5) NMK-H2, which contains the amino acid sequence ZE 10 MO: 36, and (c) NMK-NZ, which contains the amino acid sequence ZEO IU MO : 37. In some embodiments, the anti-Uaddeid1 antibody contains the sequence MH in ZEO IU MO: 33, 65, or 66, including post-translational modifications of this sequence. In some embodiments, the anti-)addei1 antibody contains the sequence MH y

ZEO IU MO: 33, including post-translational modifications of this sequence. In some embodiments, anti-Zaddeaay! the antibody contains the sequence MH in 5EO IO MO: 65, including post-translational modifications of this sequence. In some embodiments, the anti-Chaddea1 antibody contains the sequence of MH in 5EO IJOO MO: 66, including post-translational modifications of this sequence.

In another aspect, an anti-Waddey1 antibody is provided, wherein the antibody comprises a variable light chain (MI) domain having at least 90 95, 91 95, 92 95, 93 905, 94 905, 95 905, 96 95, 97 oo, 98 90, 99 90 or 100 95 sequence identity with the amino acid sequence 5EO IU

MO: 10, 26, or 34. In some embodiments, a Mi sequence having at least 90 95, 91 95, 92 95, 93 90, 94 95, 95 95, 96 95, 97 95, 98 95, or 99 95 identity comprises replacement

Zo (eg, conservative substitutions), insertions, or deletions relative to the reference sequence, but anti-

Uaddey1 antibody that contains this sequence retains the ability to bind to duddey1. In some embodiments, a total of 1 to 10 amino acids are substituted, inserted, and/or deleted in the ZEBEO IUO MO: 10, 26, or 34. In some embodiments, the substitutions, insertions, or deletions are in regions outside the NAC (ie, in the EC) . In some embodiments, MI implementation. contains one, two or three NUCs selected from (a) NMK-1 1, which contains the amino acid sequence of ZEO IU MO: 38; (c) NUNV-1I 2, which contains the amino acid sequence 5EO IYUO MO: 359; and (c) NMK-1I Z, which contains the amino acid sequence ZE IU MO: 16 or 40. In some embodiments of the invention, the anti-UZadded!1 antibody contains the sequence MI in ZEO IUO MO: 10, 26 or 34, including post-translational modifications of this sequence In some embodiments, the anti-Chaddesy!1 antibody comprises the sequence MI in 5EO IO MO: 34, including post-translational modifications of this sequence. In some embodiments of the invention, the anti-Zaddea1 antibody contains an MI sequence. in BEO IO MO: 10, including post-translational modifications of this sequence. In some embodiments of the invention, the anti-Uaddei1 antibody comprises an MI sequence. in ZEO IU

MO: 26, including post-translational modifications of this sequence.

In another aspect, an anti-)addea!1 antibody is provided, wherein the antibody comprises the MH according to each of the above embodiments and the MI. according to each of the above-mentioned variants of implementation.

In one embodiment, the antibody contains the sequences MH and MI in 5EO IJU MO: 54, where X is any amino acid except 5; and in ZEO IO MO: 34, respectively, including post-translational modifications of these sequences. In one embodiment, the antibody comprises sequences

BO MNIiMm. in 5EO IO MO: 58, where X is any amino acid except 5; and 5EO IU MO: 10, respectively, including post-translational modifications of these sequences. In one embodiment, the antibody comprises the sequences MH and MI in 5EO IO MO: 62, where X is any amino acid except

WITH; and ZEO IO MO: 26, respectively, including post-translational modifications of these sequences. In some embodiments, X is any amino acid other than 5. In some embodiments, X is any amino acid other than 5 or H. In some embodiments, X is selected from A, O, E, b, I, K, I , M, CO, EC, T, and M. In some embodiments, X is T.

In another aspect, an anti-Uaddei1 antibody is provided, wherein the antibody comprises the MN of each of the above embodiments and the MI. according to each of the above-mentioned variants of implementation.

In one embodiment, the antibody contains the sequences MH and MI in ZEO IYUO MO: 33 and 5EO IYU 60 MO: 34, respectively, including post-translational modifications of these sequences. In one embodiment, the antibody contains the sequences of MH and Mi in 5EO IU MO: 65 and 5EO IU MO: 10, respectively, including post-translational modifications of these sequences. In one embodiment, the antibody contains MH and MI sequences. in BEO IU MO: 66 and 5BEO IU MO: 26, respectively, including post-translational modifications of these sequences.

In some embodiments, the anti-daddy1 antibody comprises a heavy chain that comprises the sequence 560 IU MO:57, where X is any amino acid except 5, and a light chain that comprises the sequence ZEO IU MO:53. In some embodiments, the anti -Zaddea1 antibody includes a heavy chain that contains the sequence 5EBEO IO MO: 67, where X is any amino acid except 5, and a light chain that contains the sequence "EC IJOO MO: 75. In some embodiments, the anti-Zaddea1 antibody includes heavy chain that contains the sequence

ZEBEO IO MO: 68, where X is any amino acid except 5, and a light chain that contains the sequence 5EO AND MO: 76. In some embodiments, X is any amino acid other than 5. In some embodiments, X is is any amino acid except 5 or H. In some embodiments of the invention, X is selected from A, O, E, b, I, K, 1, M, O.K, and M. In some embodiments, X is T. In in some embodiments, the anti-Chaddea 1 antibody comprises a heavy chain that comprises the sequence BEO IO MO: 51 and a light chain that comprises the sequence ZESO I MO: 53. In some embodiments, the anti-Chaddea 1 antibody comprises a heavy chain that comprises the sequence ZEO IU MO: 52, and a light chain comprising the sequence ZEO IU MO: 53. In some embodiments, the anti-Zaddea1 antibody comprises a heavy chain comprising the sequence ZEO IU MO: 69 and a light chain comprising the sequence ZEO IU MO: 53 : 75. In some embodiments, the anti-Zaddei1 antibody contains a heavy chain g, which contains the sequence ZEO IO MO: 70, and the light chain, which contains the sequence ZEO IU MO: 76.

In an additional aspect, the present invention relates to an antibody that binds to the same epitope as the anti-Zadded1 antibody provided herein. For example, in some embodiments, an antibody that binds to the same epitope as an anti-Chaddes1 antibody is provided, which comprises the sequence MH with 5EO IO MO:33 and the sequence MI with BEO IU MO:34.

In an additional aspect, the present invention relates to an antibody that competes for binding with each of the antibodies proposed herein.

In an additional aspect of the present invention, the anti-Uaddeid1 antibody according to any of the above embodiments is a monoclonal antibody, including a chimeric, humanized, or human antibody. In one embodiment of the invention, the anti-Uaddea1 antibody is an antibody fragment, for example, Em, Rab, Rab", csEm, diantibody, or E(ab')" fragment. In another embodiment of the invention, the antibody is a full-length antibody, for example, an intact human antibody dC1 or another class or isotype of antibody described herein.

In an additional aspect, an anti-Uddaid1 antibody according to any of the above embodiments may include each of the features, individually or in combination, described in sections 1-7 below: 1. Antibody Affinity

In some embodiments, an antibody of the present invention has a dissociation constant (Ka) of "1 μM, "100 nM, "10 nM, "1 nM, "0.1 nM, "0.01 nM, or "0.001 nM (e.g., 108 M or less, e.g., 102 M to 10-73 M, e.g., 1079 M to 1073 M).

In one embodiment, Ka is measured using a radiolabeled antigen binding assay (RAI). In one embodiment, CIA is performed with the REar variant of the antibody of interest and its antigen. For example, the binding affinity of Eab to an antigen in solution is measured by equilibrating Bar using a minimal concentration of (125I)-labeled antigen in the presence of a titration series of unlabeled antigen, then capturing the bound antigen on a plate coated with an anti-Rar antibody (see example,

SNnep ei ai., (1999) U. Moi. VioI. 293: 865-881). To determine the assay conditions, MISCOTITEKF multiwell plates (Tpegto zZsipiys) are coated overnight with 5 μg/ml anti-Rar capture antibody (Surrey I arch) in 50 mM sodium carbonate (pH 9.6) and then blocked with 2,905 (w/v) gm) of bovine serum albumin in RVZ for two to five hours at room temperature (approximately 23 "C). In a non-absorbing tablet (Mips cat.Mo 269620) 100 pM or 26 pM HC-antigen is mixed with serial dilutions of the ar of interest (eg, as assessed by the anti-MESE antibody, Rar-12, in Rheuvia et al., (1997) Sapseg Ke5. 57: 4593-4599.) The Rar of interest is then incubated overnight, but incubation may be continued for longer. for a long period (e.g., about 65 hours) to ensure that equilibrium is reached. The mixtures are then transferred to a capture plate for incubation at room temperature (e.g., for one hour). The solution is then removed and the plate is washed eight times with 0, 1 with 96th polysorbate 20 (TM/ EEM-20F) in RV5. After the tablets have dried, 150 μl/well of scintillation liquid (MISKOBSIMT-207M, RabskKaga) is added, and the tablets are analyzed using a gamma counter TORSOSHMT m (RasKaga) for ten minutes. For use in competitive binding assays, the concentration of each Bar that provides binding is chosen to be less than or equal to 20 95 of the maximum binding.

According to another variant of implementation, Ka is determined by means of analyzes using surface plasmon resonance, using ViAsogeF-2000 or

VIAsogeF-3000 (VIiAsoge, Ips., Rizsaiamzhau, MU) at 25 "C using CM5 chips with immobilized antigen at "10 response units (CO). In one variant, biosensor chips from carboxymethylated dextran (SM5, ViAsoge, Ips.) activate with // M-ethyl-M'-(3-dimethylaminopropylcarbodiimide hydrochloride (EOS) and mM-hydroxysuccinimide (MH) according to the supplier's instructions. The antigen is diluted using 10 mM sodium acetate, pH 4.8, to 5 μg/ ml (70.2 μM) before administration at a flow rate of 5 μl/min to obtain approximately 10 response units (RU) of bound protein.

After antigen administration, 1 M ethanolamine is administered to block unreacted groups.

For kinetic measurements, two-fold serial dilutions of Rab (0.78-500 nM) are introduced into RV5 with 0.05 95th surfactant, polysorbate 20 (Tmeep-20"m) (RVZT) at 25 "С at a flow rate, which is approximately 25 μl/minute. The rates of association (Kop) and rates of dissociation (Kob) are calculated using the Langmuir model of simple binding in a ratio of 1:11 (VIASOKEF Emainayop Boimage megbiop 3.2) by simultaneously fitting the sensograms of association and dissociation. The dissociation constant at equilibrium (Ka) is calculated as the ratio Kopk/Kop. See, for example, Spep U. ei ai., U. Moi. Vioi 293: 865-881 (1999). If the rate of association exceeds 105 M' s" in the above analysis using surface plasmon resonance, then the rate of association can be determined using the fluorescence quenching method, which determines the increase or decrease in the intensity of the emitted fluorescence (excitation -295 nm; emission - 340 nM; band width 16 nM) at 25 "C for 20 nM antibody to antigen (Par-form) in РВ5, p 7.2, in the presence of increasing concentrations of antigen, which are measured in

From a spectrometer such as a stopped-flow spectrophotometer (Amip Ipzigitepov) or a 5IM-AMIMSO m 8000-series spectrophotometer (GPpeptozresigopis) that has a stirred cuvette. 2. Fragments of antibodies

In some embodiments, an antibody of the present invention is an antibody fragment.

Antibody fragments include, but are not limited to, Rab-, Rab'-, Rab'-5H, E(ar')'-, GU- and 5cEm-fragments, and other fragments described below. For a review of some antibody fragments, see

Nidvzop her a. May May 9: 129-134 (2003). For a review of 5cM fragments see, for example,

RinsKkiyip, in Te RPpaptasiodu oi Moposiopa! Apiibodie5, mo!. 113, Noseprigud apa Mooge eed5., (5rgipdeg/-Mepad, Mem Mogk), pp. 269-315 (1994); see also UMO 93/16185 and US Patent Nos. 5,571,894 and 5,587,458. For a discussion of Rabr and E(ab')" fragments, which contain remnants of an epitope that binds to the salvage receptor and is characterized by an increased half-life of ip mimo, see US patent Mo 5869046.

Antibodies are fragments of antibodies with two antigen-binding sites, which can be bivalent or bispecific. See, for example, EP 404097; MO 1993/01161;

Niazop ei ai., Mai. Honey. 9: 129-134 (2003); and NoiShpodeg ei ai., Rhos. May Asad 5 BOTH 90: 6444-6448 (1993). Triantibodies and tetraantibodies are also described in Niazop ei ai., Mai. May 9: 129-134 (2003).

Single-domain antibodies are fragments of antibodies that contain the complete variable domain of the heavy chain of the antibody or its section, or the complete variable domain of the light chain of the antibody or its section. In some embodiments, the single-domain antibody is a human single-domain antibody (Juotapii5, Ips., UCLA, MA; see, e.g., US Pat. No. 6,248,516, 81).

Antibody fragments can be generated using a variety of methods, including, but not limited to, proteolytic cleavage of an intact antibody, as well as production by recombinant host cells (eg, E. soy or phages), as described herein. 3. Chimeric and humanized antibodies

In some embodiments, an antibody of the present invention is a chimeric antibody. Some chimeric antibodies are described, for example, in US patent No. 4,816,567 and in Moittizopei a!., Rgos. Mai!). 60 Asad. Axes BA, 81: 6851-6855 (1984)). In one example, the chimeric antibody contains an animal variable region (eg, a variable region derived from a mouse, rat, hamster, rabbit, or non-human primate such as a monkey) and a human constant region. In an additional example, a chimeric antibody is a "class-switched" antibody in which the class or isotype has been changed from that of the parent antibody.

Chimeric antibodies include their antigen-binding fragments.

In some embodiments, the chimeric antibody is a humanized antibody. As a rule, the animal antibody is subjected to a humanization procedure to reduce immunogenicity in humans, while preserving the specificity and affinity of the animal's parent antibody. As a rule, a humanized antibody contains one or more variable domains in which the NMCs, for example, SOBCs, (or parts thereof) have their origin from an animal antibody, and the ECs (or parts thereof) have their origin from human antibody sequences. Optionally, the humanized antibody will also contain at least a portion of the constant region of the human antibody. In some embodiments, some EC residues in a humanized antibody are replaced with corresponding residues from an animal antibody (eg, an antibody from which NUK residues are taken), for example, to restore or increase the specificity or affinity of the antibody.

An overview of humanized antibodies and methods of their preparation is given, for example, in AItadgo apa Egapebop, Egopi. Viobsi 13: 1619-1633 (2008) and, in addition, they are described, for example, in

Journal of Essays, Maishge 332: 323-329 (1988); Oyeep ei ai., Rgos. May Aside. 5 BOTH 86: 10029-10033 (1989); US MoMo patents 5,821,337, 7,527,791, 6,982,321, and 7,087,409; Kazptiigi ei a!I., Method 36: 25-34 (2005) (which describes the transplantation of the defining specificity of the region (ZOK));

Radiap, Moi. And so on. 28: 489-498 (1991) (describing "surface modification"); Bag Asdtsa ei ai.,

Meiosis 36: 43-60 (2005) (describing "EC shuffling"); and O5rotst ei ai!., Meiyoa" 36: 61-68 (2005) and KiitKa ei ai!., Vg. 9). Sapseg, 83: 252-260 (2000) (describing a "directed selection" approach for EC shuffling).

Human framework regions that can be used for humanization include, but are not limited to, framework regions selected using a "best fit" method (see, e.g., et al. 9. Etc. 151: 2296 (1993)); framework regions derived from the consensus sequence for human antibodies from a specific subset of light or heavy chain variable regions (see, e.g.,

From Aside. 5 OBA, 89: 4285 (1992); and Rgesia ei ai. U. Ittipoi., 151: 2623 (1993)); framework regions of mature (somatically mutated) human immunoglobulins or framework regions of human germline immunoglobulins (see, e.g., APtadgo apa Egape5op, Egopi. Viozsi. 13: 1619-1633 (2008)); and framework regions obtained as a result of screening of EC libraries (see, for example, Vasa ei a!., y. Vioi. Spet. 272: 10678-10684 (1997) and Kozok ei ai., 9. Vioi. Spet. 271: 22611-22618 (1996)). 4. Human antibodies

In some embodiments, the antibody of the present invention is a human antibody. Human antibodies can be obtained using various methods known in the art. Human antibodies are described in general in the map riik apa map de UipKkeyi, Sit. Orip. Rnaptasoi 5: 368-74 (2001) and

Goprego, Sit. Orip. And so on. 20: 450-459 (2008).

Human antibodies can be obtained by administering an immunogen to a transgenic animal that has been modified to produce intact human antibodies or intact antibodies with human variable regions in response to antigenic exposure. Such animals typically contain all or part of human immunoglobulin loci that replace endogenous immunoglobulin loci, or that are present extrachromosomally or randomly integrated into the animal's chromosomes. In such transgenic mice, endogenous immunoglobulin loci are usually inactivated.

For an overview of methods of obtaining human antibodies from transgenic animals, see And good luck, Mai. Viotesi. 23: 1117-1125 (2005). See also, for example, US Patent Nos. 6,075,181 and 6,150,584, which describe the CHEMOMOI5BE technology: US Patent No. 5,770,429, which describes the technology

NIMAVF); US Patent No. 7041870, which describes the K-M MOSHB5EF technology, and US Patent Application Publication No. 5 2007/0061900, which describes the MEGOSIMOIOSEF technology.

Human variable regions from intact antibodies created using such animals can be further modified, for example, by combining with another human constant region.

Human antibodies can also be obtained by hybridoma-based methods. Human myeloma and mouse-human heteromyeloma cell lines for the production of human monoclonal antibodies are described. (See, for example, Korog.). Ittipoi., 133: 3001 (1984); Vgodeig ei ai., Moposiopai

Apiirodu Rgodisiip Thesppidnez5 apa Arriisaiopv5, pp. 51-63 (Magsei! OekkKeg, Ips., Mem MogK, 1987); and

Voegppeg ei ai., 9. Ittipoi., 147: 86 (1991).) Human antibodies created by hybridoma technology using human B-cells are also described in Gi ei aiI., Rgos. Mai! Asai. si. O5A, 103: 3557-3562 (2006). Additional methods include those described, for example, in US Patent No. 7,189,826 (which describes the production of DM class human monoclonal antibodies from hybridoma cell lines) and in Mi, Hiapdai Miapuihye, 26(4): 265-268 (2006) (where human-human hybridomas are described). Human hybridoma technology (Tgiot technology) is also described in Moiteg5 apa

Vgapaieip, Nivioiodu apa Nisyuraypo!odu, 20(3): 927-937 (2005) and MoPteg5 apa Vgapaieip, Mei(yoaz apa Ripaipodz ip Ehregitepia! apa Siipisa! Rnapptasoiodu, 27(3): 185-91 (2005).

Human antibodies can also be created by isolating sequences of Em clones of variable domains, which are selected from phage display libraries of human antibodies. Such variable domain sequences can then be combined with the desired human constant domain. Methods for selecting human antibodies from antibody libraries are described below. 5. Antibodies obtained from libraries

Antibodies of the present invention can be isolated by screening combinatorial libraries for antibodies with the desired activity or types of activity. For example, a number of methods of creating phage display libraries and screening such libraries for antibodies that have the desired binding characteristics are known in the art. Such methods are considered, for example, in Noodeproot ei ai. in Meipoaz ip MoiIesshiag Wiiodu 178: 1-37 (O'"Vgiep ei ai., ed., Nytap Rgez5, Toiomzha, MU, 2001) and additionally described, for example, in MeSaipe ei ai.,

Maishtsge 348: 552-554; Siaskzop evy a!., Mashte 352: 624-628 (1991); Magkz vi ai., u). My. Axes 222: 581-597 (1992); Magk5 apa Vgadrigu, in Meijoaz ip Moiesshiag Vioiyudu 248: 161-175 (10, eed., Nytap

Rgezv, Toyoua, Moscow State University, 2003); Bidpy ei ai., U. Moi. Axes 3938(2): 299-310 (2004); And ee ei ai., U. Moi. Vioi 340(5): 1073-1093 (2004); Rey Poise, Rhos. Mai). Asad 5 BOTH 101(34)3: 12467-12472 (2004); and I ee ei ai., U. Ittipoi. Meypoav5 284 (1-2): 119-132 (2004).

In some methods of phage display, sets of UN and MI genes are cloned separately by polymerase chain reaction (PCR) and recombined randomly into phage libraries that can then be screened for antigen-binding phage as described in US Pat. Chem.

Ittipoi!., 12: 433-455 (1994). As a rule, phages present fragments of antibodies on their surface, in the form of either single-chain Ru (5Cem) fragments or Har fragments. Libraries based on immunized sources provide high-affinity antibodies to the immunogen without the need for hybridoma generation. Alternatively, a set of genes can be cloned from a non-immunized source (eg, a human) to provide a single source of antibodies to a wide range of antigens that are not autoantigens, as well as autoantigens without any

From immunization, as described in the so-called ei and I.,, EMVO ., 12: 725-734 (1993). Finally, libraries based on non-immunized sources can also be obtained synthetically by cloning M gene segments from non-rearranged stem cells and using random sequence PCR primers to encode the highly variable SOCZ regions and complete the ip migo rearrangement as described in Noodeproot apa M/ipieg, U). My. Vioi!., 227: 381-388 (1992). Patents and patent application publications that describe human phage antibody libraries include, for example, US Patent No. 5,750,373 and Patent Application Publications No. 2005/0079574, 2005/0119455, 2005/0266000, 2007/0117126, 2007/0160598, 2007/0237764, 2007/0292936 and 2009/0002360.

Antibodies or antibody fragments isolated from human antibody libraries are considered in this description to be human antibodies or human antibody fragments. 6. Polyspecific antibodies

In some embodiments, the antibody of the present invention is a polyspecific antibody, for example, a bispecific antibody. Polyspecific antibodies are monoclonal antibodies that have binding specificities to at least two different sites. In some embodiments, one of the binding specificities is binding to daddesy1, and the other is binding to any other antigen. In some embodiments, bispecific antibodies can bind to two different epitopes of daddea1. Bispecific antibodies can also be used to concentrate cytotoxic agents in expressing cells

Wadded1. Bispecific antibodies can be obtained in the form of full-length antibodies or antibody fragments.

Techniques for producing polyspecific antibodies include, but are not limited to, recombinant co-expression of heavy chain-light chain pairs of two immunoglobulins that have different specificities (see Miiyieiip apa Siseiyo, Maishge 305:537 (1983)), UMO 93/08829 and

TgaipeskKeg ei aI., EMVO U. 10:3655 (1991)) and "protrusions-into-recesses" engineering (see, for example, US patent Mo 5731168). Polyspecific antibodies can also be obtained by engineering the effects of electrostatic guidance to obtain Es-heterodimeric antibody molecules (MUMO 2009/089004 At); cross-linking of two or more antibodies or fragments (see, for example, US Patent No. 4,676,980 and Vgeppapp et al., Science, 229:81 (1985)); the use of leucine zippers for the preparation of bispecific antibodies (see, for example, Kovie!pu ei ai., y. 60 Ititipoi., 148(5):1547-1553 (1992)); the use of the technology of obtaining "diantibodies" for the creation of fragments of bispecific antibodies (see, for example, Noiipdeg ei ai., Rgos. Mai!. Asad.

All together. OBA, 90:6444-6448 (1993)); and the use of dimers of single-chain Em (5Em) (see, for example, Ogybeg et al., U. Ittipoi., 152:5368 (1994)); and the preparation of trispecific antibodies, as described, for example, in Tiy ei ai. U. Ittipoi. 147:60 (1991).

This description also includes engineered antibodies with three or more functional antigen-binding sites, including "octopus antibodies" (see, for example, 5 2006/0025576 A1).

An antibody or fragment herein also includes a "dual-acting Rar" or "UAE" that contains an antigen-binding site that binds to Udaddea/1 as well as another antigen (see, e.g., WO 2008/0069820) . 7. Variants of antibodies

In some embodiments, variants of the amino acid sequences proposed in this description of antibodies are provided. For example, it may be desirable to increase the binding affinity and/or other biological properties of the antibody. Variants of the amino acid sequence of the antibody can be obtained by introducing appropriate modifications into the nucleotide sequence that encodes the antibody, or by peptide synthesis. Such modifications include, for example, deletions, and/or insertions, and/or replacement of residues in the amino acid sequences of the antibody. Any combination of deletions, insertions, and substitutions can be made to produce the final construct, provided that the final construct has the desired characteristics, such as antigen binding. a) Variants with substitutions, insertions and deletions

In some embodiments, the invention relates to antibody variants that contain one or more amino acid substitutions. The mutagenesis sites of greatest interest with replacement include NMC and EC. Conservative substitutions are listed in Table 1 under the heading "preferred substitutions". More significant changes are listed in Table 1 under the heading "typical substitutions" and are further described below with reference to amino acid side chain classes. Amino acid substitutions can be introduced into the antibody of interest and the products screened for desired activity, such as retention/increase in antigen binding, reduction in immunogenicity, or enhancement of AUC or SOC.

Coo)

Table 1 e() 111111 |beshoMarMesAyuv;Rpe Norleytsyn.//-////// Le SS tsets(Y 11 |Norleychyn;oPe; Ma; MesAv;RNe.yD/ EU

Amino acids can be divided into groups according to the common properties of their side chains: 1) hydrophobic: norleucine, Mei, Aa, Mai, Hem, Pe; 2) neutral hydrophilic: Su, Zeg, TAg, Azp, Sp;

C) acidic: A5p, Sm;

4) basic: Ni, Guv, Agu; 5) residues that affect the orientation of the chain: су, Рго; 6) aromatic: Tgr, Tug, Rie.

Non-conservative substitutions will cause a member of one of these classes to be replaced by another class.

One type of variant with substitutions involves replacing one or more residues of the hypervariable regions of the parent antibody (eg, humanized antibody or human antibody). Of course, the resulting variant(s) selected for further investigation will have changes (e.g., improvement) in some biological properties (e.g., increased affinity, decreased immunogenicity) relative to the parent antibody, and/or will substantially retain some biological properties of the parent antibody. A typical variant with substitutions is an affinity matured antibody, which can be conveniently obtained, for example, using phage display-based affinity maturation methods such as those described herein. Briefly, mutate one or more residues in

NUE and antibody variants are presented on the surface of phage and screened for specific biological activity (for example, binding affinity).

Changes (for example, substitutions) can be introduced into the NMC, for example, to increase the affinity of the antibody. Such changes can be introduced into NMC "hotspots", i.e. codon-encoded residues that are mutated at a high frequency during the somatic maturation process (see, e.g., Spouhapigu, Meijod5 Moi. Vioi. 207: 179-196 (2008)) , or the residues that come into contact with the antigen, while checking the resulting MH or Mi variant for binding affinity. Affinity maturation by construction of secondary libraries and repeated selection from them has been described, for example, by Noodeproot et al. in Meyovd5 ip MoiIesciag Bioiodo 178: 1-37 (O'Whiep et al., ed., Nytap Rge55, Toioma, MU, (2001)) In some embodiments, carrying out affinity maturation in variable region genes selected for maturation introduces diversity by using each of a number of methods (eg, error-prone PCR, strand shuffling, or mutagenesis using oligonucleotides). Then they create a secondary library. The library is then screened to identify any antibody variants with the desired affinity. Another way of introducing diversity includes approaches aimed at NMC,

In which several NUK residues are randomized (for example, 4-6 residues at a time). The NMC residues involved in antigen binding can, in particular, be identified, for example, using alanine-scanning mutagenesis or modeling. Especially, SOK-NZ and SOB-I Z often become targets.

In some embodiments, substitutions, insertions, or deletions may occur in one or more NMCs, provided that such changes do not significantly reduce the antibody's ability to bind antigen. For example, conservative changes (for example, conservative substitutions, given in this description), which do not significantly reduce the binding affinity, can be made in the NMC. Such changes may be outside the "hot spots" of the NMC. In some embodiments of the variants of the sequences of MH and Mi, given above, each NUK either remains unchanged or contains no more than one, two or three amino acid substitutions.

A suitable method for identifying residues or regions of an antibody that can be targeted for mutagenesis is called "alanine-scanning mutagenesis" described by Sippipudiat and Umeyib (Zsiepse, 244: 1081-1085 (1989)). In this method, a target residue or group of residues (eg, charged residues such as ag, azr, pi5, uz, and adm) is identified and replaced with a neutral or negatively charged amino acid (eg, alanine or polyalanine) to determine whether an effect on the interaction is detected antibodies with antigen.

Additional substitutions can be introduced at amino acid positions that demonstrate functional sensitivity to the original substitutions. Alternatively or additionally, the crystal structure of the antigen-antibody complex can be used to identify the contact points between the antibody and the antigen. Such contact points and neighboring residues can be mapped or excluded as replacement candidates. Options can be screened to determine if they have the desired properties.

Insertions (insertions) in the amino acid sequence, the length of which is in the range from one residue to polypeptides that contain a hundred or more residues, include fusions with the amino end and/or carboxyl end, as well as insertions within the sequence of one or many amino acid residues. Examples of terminal insertions include antibody with

M-terminal methionyl residue. Other insertion variants of the antibody molecule include fusion of the M- or C-terminus of the antibody with an enzyme (for example, for AOERT) or a polypeptide, which increases the half-life of the antibody in serum. b) Glycosylation variants

In some embodiments, the antibody of the present invention is modified to increase or decrease the degree of glycosylation of the antibody. Adding or removing glycosylation sites to an antibody is easily done by changing the amino acid sequence, so that one or more glycosylation sites are created or eliminated.

If the antibody contains an Eso region, the carbohydrate attached to it can be modified. Natural antibodies produced by mammalian cells usually contain a branched, fork-shaped oligosaccharide, which, as a rule, is attached by means of an M-glycosidic bond to the A5p297 CH2 domain of the E region. See, for example, Umgidni ei aiI. TIVTESN 15: 26-32 (1997).

An oligosaccharide can include various carbohydrates, for example, mannose, M-acetylglucosamine (SISMAs), galactose and sialic acid, as well as fucose attached to SIsMAs in the "stem" of a fork-like oligosaccharide structure. In some embodiments, modification of the oligosaccharide in the antibodies of the present invention may be performed in order to create variants of the antibody with some improved properties.

In one embodiment, antibody variants with a carbohydrate structure lacking fucose attached (directly or indirectly) to the E-region are provided. For example, the amount of fucose in such an antibody can be 1-80 95, 1-65 95, 5-65 95, 20-40 95. The amount of fucose is determined by calculating the average amount of fucose in the sugar chain attached to Azp297, relative to the sum of all glycostructures, attached to Azp 297 (for example, complex, hybrid structures and structures with a high amount of mannose), due to

MA! 0I-TOE mass spectrometry, for example, as described in UMO 2008/077546. A5zp297 refers to the asparagine residue, which is located approximately at position 297 in the E-region (according to the EO numbering of E-region residues); however, A5p297 may also be approximately -3 amino acids before or after position 297, i.e. between positions 294 and 300, due to slight variations in antibody sequences. Such variants of fucosylation can be characterized by improved AYUSS function. See, for example, patent application publications

US MoMo 5 2003/0157108 (Rgevia, I 3; 005 2004/0093621 (Kuosha Nakko Koduo Co., CA). In some embodiments, the IdC1 constant region that contains the M2975 or M297A mutation has essentially no effector function. Publication Examples , which relate to "defucosated" or "fucose-deficient" antibody variants, include: 5 2003/0157108; UMO 2000/61739; UMO

From 2001/29246; OB 2003/0115614; OB 2002/0164328; OB 2004/0093621; 005 2004/0132140; 5 2004/0110704; 05 2004/0110282; 005 2004/0109865; MO 2003/085119; MO 2003/084570; MO 2005/035586; MO 2005/035778; MO2005/053742; MO2002/031140; OKa?laki ei ai. U. Moi. Vioi 336: 1239-1249 (2004); Matape-OpPpyki eyi ai. Vioyesp. Vioepd. 87: 614 (2004). Examples of cell lines capable of producing defucosylated antibodies include Hes13 CHO cells incapable of fucosylating proteins (KirkKa ei ai. Agsp. Viospet. Viorpuz. 249: 533-545 (1986); patent application

USA Mo 05 2003/0157108 A, Rgezia, I; UMO 2004/056312 A1, Adatz et al., especially in example 11), and knockout cell lines, such as CHO cells with a knockout gene for alpha-1,6-fucosyltransferase, ROT8 (see, for example, Uatape-ONpiki et al. ., Bioesn. Vioepd. 87: 614 (2004); Kapaa, U. Yei a!., Vioyesn. Vioepd., 94(4): 680-688 (2006); ii UMO 2003/085107).

In addition, variants of antibodies with tridentate oligosaccharides are proposed, for example, in which SISMAc is present at the branching point of the fork-shaped oligosaccharide attached to the E region of the antibody. Such antibody variants may have reduced fucosylation and/or improved fucosylation

Arss function. Examples of such variants of antibodies are described, for example, in UMO 2003/011878 (eap-

Maigei ei aI.); US patent No. 6602684 (Shtpapa ei aI.) and 05 2005/0123546 (Shtapa ei a!.). Antibody variants with at least one galactose residue in the oligosaccharide attached to the E region are also proposed. Such antibody variants may have improved SOS function. Such variants of antibodies are described, for example, in M/O 1997/30087 (Raiyei ei aI.); UUO 1998/58964 (Kaiiy, 5.) and

MO 1999/22764 (Va|y, 5.). c) Variants of the E-region

In some embodiments, one or more amino acid modifications may be introduced into the E-region of an antibody of the present invention, thereby creating a variant of the E-region.

A variant of the Po-region may contain the sequence of the human E-region (for example, the E-region to,

I9c2, 403 or Ids4 of a person) that contains an amino acid modification (for example, a replacement) in one or more amino acid positions.

In some embodiments, the present invention provides an antibody variant that has several, but not all, effector functions, making it a desirable candidate in such applications where the half-life of an ip mmo antibody is important, and some effector functions (such as complement activation and AOSS) are unnecessary or harmful. IP migo and/or IP mimo cytotoxicity assays can be performed to confirm reduction/depletion of SOC and/or AOSSB activity. For example, Es receptor (EsSK) binding assays can be performed to ensure that the antibody does not bind Esuk (therefore, it probably lacks AUCS activity), but retains the ability to bind EsCp. The main AUCS mediating cells, MK cells, express only EsUKII, while monocytes express EsuKI, EsuKII and EsuKP. Es expression in hematopoietic cells is summarized in Table C on page 464 Kameishi apa Kipei, Appy. Chem.

And so on. 9: 477-492 (1991). Non-limiting examples of immunoassays for the assessment of AOC activity of a molecule of interest are described in US Patent No. 5,500,362 (see, e.g., Neil Bigot, 1. et al.

Rgos. May Asad bsi OBA 83: 7059-7063 (1986)) and Neibigot, I ei ai., Rgos. May Asai. 5 OBA 82: 1499-1502 (1985); Mo 5821337 (see Vgiddetapp, M. ei ai., U. Ehr. Med. 166: 1351-1361 (1987)). Alternatively, non-radioactive assay methods can be used (see, for example, ASTIM Flow Cytometry Non-Radioactive Cytotoxicity Assay (SePtesppoodu, Ips. Moshipiaip Miemu, SA); and SuiTox 969 Non-Radioactive Cytotoxicity Assay (Rgoteda, Maydihop, M/). Suitable for such assays, effector cells include peripheral blood mononuclear cells (PBMCs) and natural killers (NK).Alternatively, or additionally, the AUC activity of a molecule of interest can be assessed by mimo, for example, in an animal model such as that described in Siupez ei ai., Rgos. Mai. Asai. 5si. OBA 95: 652-656 (1998)). C14 binding assays can also be performed to confirm that the antibody is unable to bind C14 and therefore has no SOC activity. See, for example, EGISA for the assessment of the binding of SID and SZs in MO 2006/029879 and UMO 2005/100402. To assess complement activation, it is possible to conduct a SOS analysis (see, for example, Са;77апо-бапиого 6i ai., u. Ittipoi.

Meinpodz 202: 163 (1996); Stada, M.5. Yei a!., Viosa 101: 1045-1052 (2003); and Studd, M.5. apa M.).

Siepie, Viosa 103: 2738-2743 (2004)). Determination of binding to EsCp and IP beyond clearance/half-life can also be performed using methods known in the art (see, for example, Reikoma, 5.V. ei ai., Ipi. Ettipoi. 18(12): 1759 -1769 (2006)).

Antibodies with reduced effector function include antibodies with replacement of one or more residues in positions 238, 265, 269, 270, 297, 327 and 329 of the ES region (US patent Mo 6737056). Such Es-mutants include c-mutants with substitutions in two or more amino acid positions 265, 269, 270, 297 and 327, including the so-called Es-mutant "SAMA" with the replacement of residues 265 and 297 with alanine (US patent Mo 7332581).

Some variants of antibodies with increased or decreased binding to ESK have been described (see

For example, US patent No. 6737056; UMO 2004/056312 and ZPieid5 ei ai., 9. Vioi. Spent 9(2): 6591-6604 (2001)).

In some embodiments, the antibody variant contains an Es region with one or more amino acid substitutions that increase AUCS, for example, with substitutions at positions 298, 333, and/or 334 of the Pco region (EOo residue numbering).

In some embodiments, changes are made to the Es region that result in a change (ie, either an increase or a decrease) in Cd binding and/or complement-dependent cytotoxicity (CTC), for example, as described in US Pat. No. 6,194,551, M/ O 99/51642 and in

The idiosyncrasy of her ai. U. Ittipoi. 164: 4178-4184 (2000).

Antibodies with an increased half-life and increased binding to the neonatal Es receptor (EsKp), which is responsible for the transfer of maternal IDS to the fetus (syueg ei ai.,

U. Ittipoi. 117: 587 (1976) and Kit ei ai., 9. Ittipoi. 24: 249 (1994)), described in 5 2005/0014934 A1 (Nipup et al.). These antibodies contain the Eso region with one or more substitutions in it, which increase the binding of the Eso region to PsCp. Such Es region variants include Es regions with substitutions at one or more Es region residues selected from 238, 256, 265, 272, 286, 303, 305, 307, 311, 312, 317, 340, 356, 360, 362, 376, 378, 380, 382, 413, 424, and 434, for example, with a replacement of residue 434 in the ES region (US Pat. No. 7,371,826).

See also Juipsap 5 Umipieg, Mayige 322:738-740 (1988); US patent Mo 5648260; US patent

MO 5624821 and UMO 94/29351, which refer to other examples of E-region variants. a) Variants of antibodies with genetically engineered cysteine

In some embodiments, it may be desirable to create antibodies with genetically engineered cysteine, for example, "thiomate", in which one or more amino acid residues in the antibody are replaced with cysteine residues. In specific embodiments, the substituted residues occur in accessible sites of the antibody. As a result of the substitution of these residues with cysteine, the reactive thiol groups are thus located in the accessible sites of the antibody and can be used to conjugate the antibody to other molecules, such as drug agents or drug agent linkers, to create an immunoconjugate, as described below in this documents In some embodiments, any one or more of the following residues may be replaced by cysteine: M205 (Kabat numbering) of the light chain;

A118 (EO numbering) of the heavy chain and 5400 (EO numbering) in the ES region of the heavy chain.

Antibodies with genetically engineered cysteine can be created as described, for example, in US Pat

Mo 7521541. e) Derivatives of antibodies

In some embodiments, the antibody of the present invention can be further modified to contain additional non-biological molecules that are known in the art and readily available. Molecules suitable for antibody derivatization include, but are not limited to, water-soluble polymers. Non-limiting examples of water-soluble polymers include, but are not limited to, polyethylene glycol (PEG), ethylene glycol and propylene glycol copolymers, carboxymethyl cellulose, dextran, polyvinyl alcohol, polyvinylpyrrolidone, poly-1,3-dioxolane, poly-1,3,6-trioxane, ethylene copolymer and maleic anhydride, polyamino acids (or homopolymers, or random copolymers) and dextran, or poly(n-vinylpyrrolidone) polyethylene glycol, homopolymers of propylene glycol, copolymers of propylene oxide and ethylene oxide, polyoxyethylated polyhydric alcohols (for example, glycerin), polyvinyl alcohol and their mixtures. Polyethylene glycol propionaldehyde may have manufacturing advantages due to its stability in water. The polymer can have any molecular weight and can be branched or unbranched. The number of polymers attached to the antibody may vary, and when more than one polymer is attached, they may be the same or different molecules. Generally, the number and/or type of polymers used for derivatization can be determined by taking into account, for example, but not limited to: the specific properties or functions of the antibody to be improved; whether the antibody derivative will be used for treatment under certain conditions, etc.

In another embodiment, conjugates of an antibody and a non-protein molecule are proposed, which can be selectively heated under the influence of radiation. In one of the variants of the implementation, the non-protein molecule is a carbon nanotube (Kat eyi ai., Rgos. Mai. Asai. 5si. OBA 102: 11600-11605 (2005)). The radiation can be of any wavelength and includes, but is not limited to, wavelengths that do not harm normal cells, but that heat the non-protein molecule to a temperature that destroys cells that are in close proximity to the non-protein molecule antibody.

B. Recombinant methods and compositions

Zo Antibodies can be obtained using recombinant methods and compositions, for example, as described in US patent No. 4,816,567. antibody described herein. Such a nucleic acid can encode an amino acid sequence that contains an MI and/or an amino acid sequence that contains a UN of an antibody (eg, the light and/or heavy chains of an antibody). In an additional embodiment, one or more vectors (for example, expression vectors) containing such a nucleic acid are proposed. In an additional embodiment, a host cell containing such a nucleic acid is provided. In one embodiment, the host cell contains (eg, transformed by): (1) a vector that contains a nucleic acid that encodes an amino acid sequence that contains an MI. antibodies, and an amino acid sequence that contains the MH antibodies, or (2) a first vector that contains a nucleic acid that encodes an amino acid sequence that contains Mi. antibodies, and a second vector that contains a nucleic acid that encodes an amino acid sequence that contains MH antibodies. In one embodiment, the host cell is eukaryotic, e.g., a Chinese hamster ovary (CHO) cell or a lymphoid cell (e.g., a

Uo, M5O, Zr20). In one embodiment, the proposed method of manufacturing anti-

Uaddedi antibody, which involves culturing a host cell containing a nucleic acid encoding an antibody as proposed above under conditions suitable for expression of the antibody, and optionally isolating the antibody from the host cell (or cell culture medium landlady).

For recombinant production of anti-Wadded! antibody nucleic acid that encodes an antibody, for example, described above, is isolated and inserted into one or more vectors for subsequent cloning and/or expression in a host cell. Such nucleic acid can be easily isolated and sequenced using conventional procedures (for example, using oligonucleotide probes that are capable of specific binding to the genes encoding the heavy and light chains of the antibody).

Host cells suitable for cloning or expression of antibody vectors that encode include prokaryotic or eukaryotic cells described herein. For example, antibodies can be obtained in bacteria, in particular, when glycosylation and the effector function of ES are not required. For expression of antibody fragments and polypeptides in bacteria, see, 60 e.g., US Patent Nos. 5,648,237, 5,789,199, and 5,840,523. (See also Spapop, Meitoase et al.

Zo

Moiesshiag Vioiodu, Moi. 248 (V.K.S. Go, ed., Nytapa Rgevz5, Toioula, MU, 2003), pp. 245-254, where the expression of antibody fragments in E. soy is described). After expression, the antibody can be isolated from the mass of bacterial cells in the soluble fraction and can be further purified.

In addition to prokaryotes, hosts that are suitable for cloning or expressing vectors that encode antibodies are eukaryotic microorganisms such as filamentous fungi or yeasts, which include fungal and yeast strains whose glycosylation pathways have been "humanized", resulting in antibodies with partial or fully human glycosylation profile. See Segpdgo55, Mai.

Viotsn. 22: 1409-1414 (2004) and Ii eiai., Mai. Viotesp. 24: 210-215 (2006).

Host cells suitable for expression of glycosylated antibodies are also obtained from multicellular organisms (invertebrates and vertebrates). Examples of invertebrate cells include plant and insect cells. Numerous strains of baculoviruses have been identified that can be used with insect cells, in particular, to transfect cells from Zrodoriega Ihydiregaa.

Plant cell cultures can also be used as hosts. See, for example, US Patent Nos. 5,959,177, 6,040,498, 6,420,548, 7,125,978, and 6,417,429 (which describe the technology

RIG AMTIVOOIE5 m for obtaining antibodies in transgenic plants).

Vertebrate cells can also be used as hosts. For example, mammalian cell lines that are adapted to growth in suspension can be used. Other examples of mammalian host cell lines used are the monkey kidney CMT line, transformed 540 (СО05-7); human embryonic kidney cell line (293 or 293 cells described in Sgapat et al.,

U. Zep Migoii. 36:59 (1977)); baby hamster kidney cells (HKN); mouse Sertoli tumor cells (TMA4 cells described, for example, in Maipeg, Viol. Nergo. 23: 243-251 (1980)); monkey kidney cells (CM); African green monkey kidney cells (MEKO-76); human cervical carcinoma cells (HCC); dog kidney cells (MSC); gray rat liver cells (VKI. ZA); human lung cells (M/138); human liver cells (Ner 02); mouse mammary tumor (MMT 060562); TKI cells, described, for example, in MaiNeg ei ai., Appa!5 M.U. Asai. from 383: 44-68 (1982); MKS 5 cells and E54 cells. Other mammalian host cell lines used include Chinese Hamster Ovary (HNO) cells, including ONEK-HNO cells (pub. ei ai., Rgos. maj. Asad. Zsi. OBA 77: 4216 (1980)); and myeloma cell lines such as MO, M5O and 5p2/0. For a review of some mammalian host cell lines suitable for producing antibodies, see, for example, Wagaki apa

We, Meipod3z ip MyIesciag Vioiodu, My. 248 (V.K.S. I o, ed., Nytapa Rgezv, Toioma, MU), pp. 255-268 (2003).

C. Methods of analysis

Anti-Udded1i antibodies proposed in this document can be identified, screened or characterized for their physicochemical properties and/or biological activity using various methods of analysis known in the art. 1. Binding analysis methods and other analysis methods

In one aspect, the antibody of the invention is tested for antigen binding activity, for example, using known methods such as EG I5A, Western blotting, etc.

In another aspect, competitive analysis methods can be used to identify an antibody that competes with antibody A, A1, A-2, or AT (5101T) for binding to human or mouse dadded1. In some embodiments, such a competing antibody binds to the same epitope (eg, a linear or conformational epitope) that binds A, A1, A-2, or A1 (51017).

Detailed examples of methods of mapping the epitope to which the antibody binds are given in

Mogtih5 (1996) "Eriore Marripd Rgoiosoi5", in Meipod5 ip MoiIesciag Vioiodu moi. 66 (Nytapa Rgez5,

Toyuua, M).

In an illustrative competition assay, immobilized Addea1 is incubated in a solution containing a first labeled antibody that binds to Addea1 (eg, A, AT, A-2, or A1 (51017T)) and a second unlabeled antibody that is assayed for its ability to compete with the first antibody for binding to Chdaddeai!. The second antibody may be present in the supernatant of the hybridoma. As a control, immobilized daddei!1 is incubated with a solution containing the first labeled antibody, but without the second unlabeled antibody. After incubation in conditions that allow the binding of the first antibody to Chdaded1, the excess unbound antibody is removed, and the amount of label bound to the immobilized Dadded1 is measured. If the amount of label corresponding to immobilized daddea1 is significantly reduced in the test sample compared to the control sample, this indicates that the second antibody competes with the first antibody for binding to daddea1. See Nagiozh apa IGape (1988) Apiirodiev: And I arogaiogu Mapiai! issue 14 (Soy

Zrgipd Narog I arogaiyogu, Soia 5rgipd Naibog, MU). 60 2. Activity analysis methods

In one aspect, methods of analysis are proposed for the identification of anti-Uadded1 antibodies that have biological activity. Biological activity may include, for example, inhibition of Uaddeia1-induced Moisp1 signaling pathway. In some other embodiments, an antibody of the invention is tested for its ability to inhibit the expression of a reporter gene that responds to the daddea1-induced Moisp1 signaling pathway. Non-limiting examples of analysis methods are given in the examples. In some embodiments, an antibody of the invention is tested for such biological activity. Antibodies that have such biological activity as ip mimo and/or ip miigo are also proposed.

O. Immunoconjugates

The invention also provides immunoconjugates that contain an anti-Waddey antibody conjugated to one or more cytotoxic agents, such as chemotherapeutic agents or medicinal compounds, growth inhibitors, toxins (eg, protein toxins, enzymatically active toxins of bacterial, fungal, plant or of animal origin or their fragments) or radioactive isotopes.

In one embodiment, the immunoconjugate is an antibody-drug conjugate (ABS), wherein the antibody is attached to one or more drugs, including, without limitation, maytansinoid (see US Patent Nos. 5,208,020, 5,416,064 and

European patent EP 0425235 B1); auristatin, such as the monomethylauristatin drugs OE and OB (MMAE and MMARE) (see US Patent Nos. 5,635,483 and 5,780,588 and 7,498,298); dolastatin; calicheamicin or its derivatives (see US Patent Nos. 5712374, 5714586, 5739116, 5767285, 5770701, 5770710, 5773001 and 5877296; Niptap et al., Sapseg Ke5. 53:3336-3342 (1993); and

Gode sei ai., Sapseg Nevz. 58:2925-2928 (1998)); an anthracycline such as daunomycin or doxorubicin (see Kgaich et al., Sstepi Med. Spect. 13:477-523 (2006); Uenteeu et al., Viogdapis 8

Honey. Spent I etsyegz 16:358-362 (2006); Then you a!., Viosop). Snet 16:717-721 (2005); Maadu evi ai.,

Rgos. May Asad bsi BOTH 97:829-834 (2000); Byrom/snikK eyi ai!., Vioogu. May 5. Spent I eCegv 12:1529-1532 (2002); Kipo ei ai., U. Med. Spent 45:4336-4343 (2002); and US patent Mo 6630579); methotrexate; vindesine; a taxane such as docetaxel, paclitaxel, larotaxel, tesetaxel and orthotaxel; trichothecene and CC1065.

In another embodiment, the immunoconjugate contains the antibody described in this document,

Zo is conjugated to an enzymatically active toxin or fragment thereof, including, without limitation, diphtheria toxin A-chain, which does not bind active diphtheria toxin fragments, exotoxin A-chain (Rhendotopavh aegidiposa), ricin A-chain, abrin A-chain , A-chain of modexin, alpha-sarcin, proteins of AiYiIepygiez Togaii, dianthin proteins (from cloves), proteins from

Rpuiase ategisapa (RARI, RARII and PAP-5), an inhibitor from Motogais spagapiia, curcin, crotin, an inhibitor from bZaraopagia oisipaiih, gelonin, mitogelin, restrictocin, phenomycin, enomycin and trichothecenes.

In another embodiment, the immunoconjugate contains the antibody described in this document, conjugated with a radioactive atom to obtain a radioactive conjugate. A number of radioactive isotopes can be used to obtain radioactive conjugates. Examples of these include A, 1191, 125, y, Be"86 De"88, 5p!"53, Bi212, reg, pre": and radioactive isotopes I 0. If the radioactive conjugate is used for detection, it may contain a radioactive atom , which is used in scintigraphic studies, such as is99t or 1123, or a spin label used for nuclear magnetic resonance (NMR) imaging (also known as magnetic resonance imaging, MRI), such as, again, iodine-123, iodine-131, indium-111, fluorine-19, carbon-13, nitrogen-15, oxygen-17, gadolinium, manganese or iron.

Antibody conjugates with a cytotoxic agent can be prepared using a number of bifunctional protein-binding agents, such as M-succinimidyl-3-(2-pyridyldithio)propionate (5POP), succinimidyl-4-(M-maleimidomethyl)cyclohexane-1 -carboxylate (ZMSOSS), iminothiolane (IT), bifunctional derivatives of complex imidoesters (such as dimethyl adipimidate NS), activated esters (such as disuccinimidyl suberate), aldehydes (such as glutaraldehyde), bis-azido compounds (such as bis(p-azidobenzoyl hexanediamine), bis-diazonium derivatives (such as bis-(p-diazoniumbenzoyl)ethylenediamine), diisocyanates (such as toluene 2,6-diisocyanate) and bisactive fluorine compounds (such as 1,5-difluoro-2,4-dinitrobenzene) . For example, the immunotoxin ricin can be obtained by the method described in MiieNa ei ai.,, Siepse 238:1098 (1987). Carbon-14-labeled 1-isothiocyanatobenzyl-3-methyldiethylene triaminepentaacetic acid (MX-OTRA) is an example of a chelating agent used to attach a radionuclide to an antibody.

See UMO 94/11026. The linker can be a "cleavable linker" that facilitates the release of the cytotoxic agent into the cell. For example, an acid-sensitive linker, a peptidase-sensitive linker, a photolabile linker, a dimethyl linker, or a disulfide-containing linker can be used (Spagi et al., Sapseg Ke5. 52:127 -131 (1992); US Pat. Mo

Immunoconjugates or AOCs described herein expressly mean, without limitation, conjugates obtained using cross-linking reagents, including, without limitation, BMR5, EMOS5, ZMV5, NVMU5, and C-5MOS , MV5, MRVN, 5VAR, IA,

ЗИАВ, 5МСС, ЗМРВ, ЗМРН, sulfo-ЕМС5, sulfo-ЗМВ5, sulfo-КМИ5, sulfo-МВ5, sulfo-BIAV, sulfo-ЗМСС and sulfo-ЗМРВ, as well as 5М5В (succinimidyl-(4-vinylsulfone)benzoate), which are commercially available (e.g., from Riegse Wioiespoiodu, Ips.,

Voskoga, I., 0.5.A).

E. Methods and compositions for diagnosis and detection

In some embodiments, each of the anti-Udded1 antibodies provided herein is useful for detecting the presence of dhadded1 in a biological sample. As used herein, the term "detection" includes either quantitative or qualitative detection. In some embodiments, the biological sample comprises a cell or tissue, such as tumor tissue.

In one embodiment, the proposed anti-Uddaid! an antibody for use in a detection method or diagnosis. In yet another aspect, a method of detecting the presence of Uaddea!1 in a biological sample is provided. In some embodiments, the method includes providing contact of a biological sample with an anti-Uaddea1 antibody, which is described in this document, under conditions that allow binding of an anti-Uaddea1 antibody to Uaddea1, and detecting the formation of a complex between an anti-Uaddea1 antibody and Daddea 1. This method can be ip migo or ip mimo. In one embodiment, the anti-Uaddey 1 antibody is used to select subjects suitable for treatment using anti-)addey! antibodies, for example, where dadday1 is a biomarker for patient selection.

Examples of diseases that can be diagnosed using an antibody of the invention include cancer, for example, breast cancer, lung cancer, brain cancer, cervical cancer, colon cancer, liver cancer, bile duct cancer, pancreatic cancer, skin cancer , B-cell malignant neoplasms and T-cell malignant neoplasms.

In some embodiments, labeled anti-Uadde4y1 antibodies are provided. Labels include, but are not limited to, labels or molecules that are directly detected (e.g.,

(e.g., fluorescent, chromophoric, electron-dense, chemiluminescent, and radioactive labels), as well as residues such as enzymes or ligands that are detected indirectly, for example, by an enzymatic reaction or molecular interaction. Illustrative labels include, but are not limited to, radioisotopes 32P, 140, 125I, 3H and 1911, fluorophores such as rare earth chelates or fluorescein and its derivatives, rhodamine and its derivatives, dansyl, umbelliferone, luciferases such as firefly luciferase and bacterial luciferase (US patent Mo 4737456), luciferin, 2,3-dihydrophthalazinediones, horseradish peroxidase (HER), alkaline phosphatase,

B-galactosidases, glucoamylases, lysozyme, saccharide oxidases such as glucose oxidase, galactose oxidase and glucose-6-phosphate dehydrogenase, heterocyclic oxidases such as uricase and xanthine oxidase, coupled to an enzyme that uses hydrogen peroxide to oxidize a dye precursor such as HER, lactoperoxidase or microperoxidase, biotin/avidin, spin labels, bacteriophage labels, stable free radicals, etc.

E. Pharmaceutical formulations

Pharmaceutical compositions containing an anti-Udded!i antibody described herein are prepared by mixing such antibody, which has a desired degree of purity, with one or more optional pharmaceutically acceptable carriers (Kepipdiopye Rnaptasekiisai!

Zsiepse5 161 eyyyop, O5o0I, A. Ei. (1980)) in the form of lyophilized preparations or aqueous solutions. Pharmaceutically acceptable carriers are usually non-toxic to recipients in the doses and concentrations used and include, without limitation: buffers, for example, based on phosphoric, citric and other organic acids; antioxidants, including ascorbic acid and methionine; preservatives (such as octadecyldimethylbenzylammonium chloride; hexamethonium chloride; benzalkonium chloride; benzethonium chloride; phenol, butyl or benzyl alcohol; alkylparabens such as methyl- or propylparaben; catechol; resorcinol; cyclohexanol; 3-pentanol; and m-cresol); low molecular weight (less than about 10 residues) polypeptides; proteins such as serum albumin, gelatin or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, histidine, arginine or lysine; monosaccharides, disaccharides and other carbohydrates, which include glucose, mannose or dextrins; chelating agents, such as EHUOTA; sugars such as sucrose, mannitol, trehalose or sorbitol; salt-forming counterions such as sodium; metal complexes (for example, 2p-protein complexes); and/or nonionic surfactants such as polyethylene glycol (PEb). 60 Examples of pharmaceutically acceptable carriers according to the present invention additionally include agents that provide intratissue distribution of drugs, such as soluble neutrally active hyaluronidase glycoproteins (5NABESR), for example, human soluble hyaluronidase glycoproteins RIN-20, such as GNiIRN2gO (NM EMEHF, Vahieg Ipiegpaiopai , Ips.). Some examples of 5НА5БЕРО and methods of their use, including гНиРН2О, are described in US patent publications MoMo 2005/0260186 and 2006/0104968. In one aspect, ZNABESR is combined with one or more other glucosaminoglycanases, such as chondroitinase.

Examples of lyophilized formulations of antibodies are described in US patent Mo 6267958. Aqueous formulations of antibodies include the formulations described in US patent Mo 6171586 and UUO2006/044908, and the latter formulations contain a histidine-acetate buffer.

The composition according to the present invention may also contain several active ingredients, if necessary for a specific indication for treatment, preferably so that the activity of such ingredients complements each other and does not adversely affect each other. For example, additional administration of a cytotoxic agent, such as a chemotherapeutic agent, may be desirable. Such active ingredients are preferably present in combination in amounts effective for a given purpose.

Active ingredients can be placed in microcapsules obtained, for example, by coacervation methods or by interfacial polymerization, for example, hydroxymethylcellulose or gelatin microcapsules and poly-(methyl methacrylate) microcapsules, respectively, in colloidal drug delivery systems (such as liposomes, albumin microspheres, microemulsions , nanoparticles and nanocapsules) or in a macroemulsion. Such methods are disclosed in Ketipaiop'b

Ripaptaseciisa! bsiepsez 161st Yediyop, Ozoi, A. Es. (1980).

You can get drugs with a delayed release. Similar examples of drugs with delayed release include semi-permeable matrices of solid hydrophobic polymers that contain an antibody, and these matrices can be molded products such as films or microcapsules.

Formulations intended for ip injection are usually sterile. Sterility can easily be achieved, for example, by filtration through sterile filter membranes. b. Therapeutic methods and compositions

Each of the anti-Uddaid1 antibodies proposed in this invention can be used in therapeutic methods.

In one aspect, an anti-Uaddei!1 antibody for use as a medicament is provided. In other aspects, an anti-)addei1 antibody is provided for use in the treatment of a disease or disorder associated with a disrupted Moisp signaling pathway, such as cancer. In some embodiments, an anti-)addei1 antibody is provided for use in a method of treatment. In some embodiments, the present invention provides an anti-Chaddes1 antibody for use in a method of treating an individual having cancer, comprising administering to the individual an effective amount of an anti-Chaddes1 antibody. In one such embodiment of the invention, the method further comprises administering to the individual an effective amount of at least one additional therapeutic agent, for example as described below. In one such embodiment of the invention, the method further comprises administering to the individual an effective amount of at least one additional therapeutic agent, for example as described below.

In additional embodiments, the invention relates to anti-Wadded! antibodies for use in inhibiting the growth of lung cancer. In some embodiments, the present invention relates to an anti-Udded1 antibody for use in a method of reducing the growth of lung cancer in an individual, which comprises administering to the individual an effective amount of an anti-Udded1 antibody to reduce the growth of lung cancer. In some embodiments, the present invention relates to anti-

Uaddedi antibodies for use in a method of reducing the growth of breast cancer in an individual, which comprises administering to the individual an effective amount of an anti-Uadded1 antibody to reduce the growth of breast cancer. "Individual" according to each of the above variants of implementation, preferably, is a person.

In some embodiments, an anti-Uaddei1 antibody is provided for the treatment of allergy, asthma, autoimmune disease, diseases associated with goblet cell metaplasia (eg, in the lungs) and/or excess mucus. Other allergic diseases that can be treated using the anti-Waddey1 antibodies provided herein include, but are not limited to, allergic rhinitis, atopic dermatitis, food hypersensitivity, and urticaria; immune-mediated skin diseases, including bullous skin diseases, erythema multiforme and contact dermatitis; autoimmune diseases including psoriasis, rheumatoid arthritis, juvenile chronic arthritis; inflammatory bowel diseases (for example, non-specific ulcerative colitis, Crohn's disease); idiopathic interstitial pneumonia, diseases associated with goblet cell metaplasia (such as asthma, COPD, cystic fibrosis and Barrett's esophagus), pulmonary diseases such as cystic fibrosis, gluten-sensitive enteropathy and Whipple's disease; immunological diseases of the lungs, such as eosinophilic pneumonia, idiopathic pulmonary fibrosis and allergic pneumonitis; chronic obstructive pulmonary disease, RSV infection, uveitis, scleroderma, osteoporosis and lymphoma

Hodgkin.

In an additional aspect, the present invention relates to the use of an anti-Uaddei1 antibody in the manufacture or manufacture of a medicinal product. In one embodiment, the drug is intended to treat a disease or disorder associated with the disorder

Moisp-signal way. In one embodiment, the drug is for the treatment of cancer. In an additional embodiment, the drug is for use in a method of treating cancer, which comprises administering to an individual having cancer, an effective amount of the drug. In one such embodiment of the invention, the method further includes administering to the individual an effective amount of at least one additional therapeutic agent, for example, described below. An "individual" according to each of the above embodiments can be a person.

In an additional aspect, the present invention relates to a method of treating a disease or disorder associated with a disrupted Moisp signaling pathway. In one embodiment, the method comprises administering to a subject having such a disease or disorder an effective amount of an anti-Udded1 antibody. In one embodiment, the method comprises administering to a subject having cancer an effective amount of an anti-Udded1 antibody. In one such embodiment of the invention, the method further comprises administering to the individual an effective amount of at least one additional therapeutic agent, as described below. In one such embodiment of the invention, the method further comprises administering to the individual an effective amount of at least one additional therapeutic agent, as described below. An "individual" according to each of the above embodiments can be a person.

In an additional aspect, the present invention relates to a method of inhibiting the growth of cancer cells in an individual. In one embodiment, the method comprises administering to the individual an effective amount of anti-Wadded! antibodies to inhibit the growth of cancer cells. In one embodiment, an “individual” is a human.

In some embodiments, the present invention relates to methods of treating, in an individual, an allergy to asthma, an autoimmune disease, diseases associated with goblet cell metaplasia (eg, in the lungs) and/or excess mucus in an individual. In some embodiments, the present invention relates to methods of treating allergic rhinitis, atopic dermatitis, food hypersensitivity and urticaria; immune-mediated skin diseases, including bullous skin diseases, erythema multiforme and contact dermatitis; autoimmune diseases, including psoriasis, rheumatoid arthritis, juvenile chronic arthritis; inflammatory bowel diseases (for example, nonspecific ulcerative colitis, Crohn's disease); idiopathic interstitial pneumonia, diseases associated with goblet cell metaplasia (such as asthma, COPD, cystic fibrosis and Barrett's esophagus), lung diseases such as cystic fibrosis, gluten-sensitive enteropathy and

Whipple; immunological diseases of the lungs, such as eosinophilic pneumonia, idiopathic pulmonary fibrosis and allergic pneumonitis; chronic obstructive pulmonary disease, RSV infection, uveitis, scleroderma, osteoporosis and/or Hodgkin's lymphoma. In some embodiments, the method includes administering to the individual an effective amount of the anti-Uaddei1 antibody, RSOV given in this description. In some embodiments, the “individual” is a human.

In an additional aspect, the present invention relates to pharmaceutical compositions that contain each of the anti-Udded1 antibodies provided in this description, for example, for use in each of the above-mentioned therapeutic methods. In one embodiment, the pharmaceutical composition contains each of the anti-Uaddeid1 antibodies described herein and a pharmaceutically acceptable carrier. In another embodiment, the pharmaceutical composition contains each of the anti-

Uadded1 antibodies of this description and at least one additional therapeutic agent, for example, as described below.

The antibodies of the invention can be used in therapy either alone or in combination with other agents. For example, an antibody of the invention may be co-administered with at least one additional therapeutic agent. In some embodiments, the additional therapeutic agent is a cytotoxic agent. In some embodiments, the additional therapeutic agent is an antibody.

Such combined therapeutic methods, as mentioned above, include combined administration 60 (where two or more therapeutic agents are included in the same formulation or in separate formulations) and separate administration, in which case the administration of the antibody of the invention may occur before, simultaneously, or after the administration of an additional therapeutic agent or agents. In one embodiment, administration of the anti-Zadd1 antibody and administration of the additional therapeutic agent occurs within about one month, or within one, two, or three weeks, or within about one, two, three, four, five, or six days between them Antibodies of the invention can also be used in combination with radiation therapy.

The antibody of the invention (and any additional therapeutic agent) can be administered by any suitable means, including parenteral, intrapulmonary and nasal, and, if desired for local treatment, intrathecal administration. Parenteral infusions include intramuscular, intravenous, intraarterial, intraperitoneal, or subcutaneous administration. Administration may be by any suitable route, for example by injection, such as intravenous or subcutaneous injection, depending in part on whether the administration will be short or chronic. Various administration schemes are contemplated by the present invention, including, but not limited to, single or multiple administrations at various intervals, bolus administration, and pulsed infusion.

Antibodies according to this invention should be included in the pharmaceutical composition, dosed and administered in accordance with good medical practice. Factors considered in this context include the particular species of disease to be treated, the particular species of mammal to be treated, the clinical condition of the individual patient, the cause of the disease, the site of delivery of the agent, the method of administration, the schedule of administration, and other factors known to physicians who practice The antibody may optionally be included in the pharmaceutical composition together with one or more agents currently used for the prevention or treatment of the specified disease. The effective amount of such other agents depends on the amount of antibody present in the composition, the type of disease or treatment, and other factors discussed above. They are typically used in the dosages and with the methods of administration described herein, or in an amount that is from about 1 to 99 95 of the dosages described herein, or in any dosage and with any method of administration selected empirically/clinically.

For the prevention or treatment of a disease, the appropriate dosage of the antibody of the present invention (used alone or in combination with one or more other additional therapeutic agents) depends on the type of disease to be treated, the type of antibody, the severity and course of the disease, the purpose (prophylactic or therapeutic) of administration antibodies that precede therapy, the patient's clinical history and response to antibodies, as well as from the decision of the treating physician. The antibody can be administered to the patient once or in several doses.

Depending on the type and severity of the disease, a suitable initial dose to the patient may be from about 1 μg/kg to 15 mg/kg (eg, 0.1-10 mg/kg) of antibody, for example, in one or more doses, or by continuous infusions A typical daily dose can vary from about 1 mcg/kg to 100 mg/kg or more, depending on the above factors. In the case of repeated administration for several days or longer, depending on the state of treatment, as a rule, it is carried out until the desired degree of suppression of the symptoms of the disease is achieved. A typical antibody dose is in the range of approximately 0.05 to 10 mg/kg.

Thus, one or more doses of about 0.5 mg/kg, 2.0 mg/kg, 4.0 mg/kg, or 10 mg/kg (or any combination thereof) can be administered to the patient. Such doses can be administered at defined time intervals, for example, weekly or every three weeks (eg, so that the patient receives from about two to twenty, or, for example, about six doses of the antibody).

An initial higher loading dose may be administered, followed by one or more low doses. An exemplary administration schedule includes the administration of an initial loading dose of about 4 mg/kg, followed by a weekly maintenance dose of about 2 mg/kg of antibody. However, other input schemes can be used. The results of this therapy can be easily monitored using traditional methods and analyses.

It is obvious that any of the above compositions or therapeutic methods can be carried out using the immunoconjugate of the invention instead of or in addition to anti-

Uaddea1 antibodies.

N. Industrial products

In another aspect of the invention, industrial products are proposed, which include substances useful for the treatment, prevention and/or diagnosis of the diseases described above. This industrial product includes a container and a label or leaflet on or associated with the container. Suitable containers include, for example, vials, vials, syringes, bags for IV solutions, etc. These containers can be made of various materials, such as glass or plastic. The container contains a composition that, by itself or in combination with another composition, is effective in the treatment, prevention, or diagnosis of a given condition, and may have a sterile inlet (for example, the container may be an IV bag or a vial having plug, which is pierced with a hypodermic needle). At least one active agent in this composition is an antibody of the present invention. The label or package insert states that the formulation is intended for use in the treatment of the selected condition. Moreover, the industrial product may contain: (a) a first container with a composition contained therein, where this composition contains an antibody according to the invention; and (b) a second container with a composition contained therein, wherein the composition contains an additional cytotoxic or other therapeutic agent.

The industrial product in this embodiment of the invention may additionally contain a leaflet-insert, in which it is stated that the composition can be used in the treatment of a certain condition. Alternatively or additionally, the industrial product may additionally contain a second (or third) container that contains a pharmaceutically acceptable buffer, such as bacteriostatic water for injection (BWIP), phosphate-buffered saline, Ringer's solution, and SO solution -glucose. It may also contain other materials and substances required from a commercial and consumer point of view, including other buffers, diluents, filters, needles and syringes.

It is obvious that each of the above industrial products can include an immunoconjugate according to the invention instead of or in addition to the anti-Daddey1 antibody.

I. EXAMPLES

Below are examples of methods and compositions according to the invention. It is clear that various other implementations may be implemented in practice, taking into account the general description given above.

Example 1. Preparation of anti-Uaddea antibodies. and. Sorting and screening the library for the identification of anti-Daddyd1 antibodies

Human antibody phage libraries with synthetically generated diversity in selected complementarity-determining regions that mimic the natural diversity of the human dO repertoire were used to screen Bar fragments that are presented on the surface of bacteriophage M13 particles. Dadi1- was used as an antigen for sorting the library

From human 0О5I-ЕСЕ1-4 (ZEO IYUO MO: 6) or human dad2-051-ЕСИЕ1-4 (ZEO IYU MO: 8). Mips MahibZogr 96-well plates for immunological studies were coated overnight at 4 °C with the target antigen (10 μg/ml) and blocked for 1 hour at room temperature with phage-blocking PB5T buffer (phosphate-buffered saline (PB5) with 1 95-m (wt./0b.) bovine serum albumin (BBA) and 0.05 95-m (06./06.) Tmeep-20. Phage libraries of MN regions of antibodies (see, for example, ai., 9. Ittipoi. Meii. 284:119-132 (2004)) and MN/LI -regions (see Giapdei aiI., UMVB. 366: 815-829 (2007)) were added to antigen-coated tablets separately and incubated overnight at room temperature. The next day, the antigen-coated plates were washed ten times using RVT (RVZ with 0.05 95

Tmeep-20), and the phages that bound were eluted using 50 mM HCl and 500 mM Mass for 30 min and neutralized with an equal volume of 1M Ttiz buffer (pH 7.5). The isolated phages were amplified in cells of E. soy XI-1 Vise. In subsequent rounds of selection, the incubation time of phage antibodies on antigen-coated tablets was reduced to 2-3 hours and the hardness of washing the tablets was gradually increased.

After 4 rounds of screening, significant enrichment was observed. 96 clones were selected from each MN and MN/M libraries to determine whether they specifically bind to human Uadde1 or dadded2. The variable regions of these clones were PCR-sequenced to identify clones with unique sequences. The affinity of the phage antibodies was ranked using a single-point competitive EGISA. IC values for phage antibodies were additionally determined using competitive EGISA. Unique phage antibodies that specifically bind to human Uaddea1 (but not daddea2), Uhaddea2 (but not daddea1), or both daddea!1 and dhaddea2 were selected and reformatted into full-length dos for evaluation in cellular assays of ip myigo cells.

The clones of interest were reformatted in ED) by cloning the Mi and Mn regions of individual clones into a rKK vector for expression in mammalian cells (RKK. ROZ. NitapkKarra), which contains the human kappa chain constant domain, and an expression vector (RKK . PO4.Nitapns), which encodes the full-length constant domain of human IdO1, respectively (Zpieiia5 ei ai.,. Vioi!

Spent 2000; 276: 6591-6604). Then the antibodies were transiently expressed in mammalian CHO cells, and purified using a column with A. r protein. Construction of libraries to increase the affinity of clones obtained from Mn- or Mnmi- (510) libraries

Phagemid po703, obtained from phagemid po350-265 (I ee ei ai., U. Moi. Vioi 340, 1073-1093 (2004), which contains a stop codon (TAA) in all positions of SOC-I Z and which represents monovalent Rab on the surface of bacteriophage M13) served as a library template for transferring heavy chain (Mn) variable domains of clones of interest from the Mn library for affinity maturation.

Both hard and soft randomization strategies were used for affinity maturation. For hard randomization, a library of single-stranded light chains with selected positions of three

The light chain SOC was randomized using amino acids selected to mimic natural human antibodies, and the selected DNA degeneracy was as described in Section 1. (9.

MY. Vio! 340, 1073-1093 (2004)). To achieve mild randomization conditions that introduce mutations at selected positions with a frequency of approximately 50 95, mutant DNA was synthesized with base mixtures in the ratio 70-10-10-10 in favor of wild-type nucleotides (SaPPor ei ai., doigpai oi Measipa!

Spetiwig 37:1233-1251 (1994)). For soft randomization, the targets were residues in positions 91-96 of SOC-I 3, 30-33, 35 of SOCK-NI, 50, 52, 53-54 and 56 of SOC-H2, 95-98 of SON-NZ ; and for randomization, three different combinations of SOK loops, NI/ 3, H2/ 3, apa NZ/ 3 were selected.

For clones obtained from the Mnmi library, phagemids containing 4 stop codons (TAA) in each

SOCs representing monovalent Rab on the surface of bacteriophage M13 were obtained individually and served as a matrix for mutagenesis by KipKe! for the construction of the library for affinity maturation For clones obtained from the MnMmi library, only a soft randomization strategy was used, and the SOC-I C diversity was generated in a naïve library To achieve soft randomization conditions, the targets were residues at positions 28-31 of SOMK-I 1, 50, 53-55 with SOK-I2, 91-96 with SOK-I 3, 30-35 with SOK-NI, 50-56 with SOK-NEO, 95-100 with SOB-NZ; and four different combinations of loops NIL 3", H2/L 37", as well as NZ/I 37 and I 1/.2/ were selected for randomization. 37 (where 7" denotes the position of stop codons in the matrix). p. Phage sorting strategy to achieve increased affinity

To select antibodies with improved affinity, Chdadi or Dad2 antigens were first biotinylated with a limited amount of reagent. One round of phage library sorting on tablets and five rounds of sorting in solution with increasing hardness were carried out. For the first round of plate sorting, 10 μg/ml of antigen was first plated on Mahizogr plates and preblocked using blocking buffer (1 95 VZA and 0.05 95 Tmeep-20 in

From RV5). C Ob/ml phages in blocking buffer were incubated with antigen on plates for 3 hours. Wells were washed ten times with RVZ-0.05 95 Gueep-20. Bound phage was eluted in 150 μl per well of 50 mM HCl/500 mM CS for 30 min and then neutralized with 50 μl per well of 1M

Tris, pH 8, was titrated and propagated for the next round. In subsequent rounds, screening of phage libraries was performed in solution, where the phage library was incubated with 100 nM biotinylated target protein (concentration based on the IChoo value of the parent phage clone) in 100 μl of a buffer containing 1 95-Zyregriosc (Riegse Vioyesppoiiodu) and 0 ,05,905

Tmeep-20, for 2 hours at room temperature. The mixture was further diluted 10-fold with 1 95% Z,regbiosk and 100 μl per well was applied to wells coated with neutravidin (10 μg/ml) for 30 minutes at room temperature with gentle shaking. To determine background binding, control wells containing phages were left on plates coated with neutravidin. Bound phages were then washed, eluted and propagated as described for the first round. Five more rounds of sorting in the solution were carried out in parallel with increasing the hardness of the selection. Of which the first pair of rounds were designed to select for rate of association by reducing the concentration of biotinylated target protein from 00 nM to 0.1 nM, and the last two rounds were designed to select for rate of dissociation by adding an excess of non-biotinylated target protein ( from 300 to 1000-fold excess) to screen out weak coupling agents at room temperature. and. EGIZA for high-throughput affinity screening (single-point competitive assay)

Colonies were selected in the sixth round of screening. Colonies were grown overnight at 37 °C in 150 μl/well in 2UT medium with the addition of 50 μg/ml carbenicillin and 1x10 μg/ml M1IZ3KO?7 in a 96-well plate (Rysop). From the same plate, a colony of Hi was selected as a control -1, infected with the parental phage. 96-well Mips Mahizogr plates were coated with 100 μl/well of dad1i or dad2 (0.5 μg/ml each) in RVZ at 4 °C overnight. Tablets were blocked with 150 μl of 1 95 VZA and 0.05 9 rb Tzheep-20 in RV5 for 1 hour. 35 μl of phage supernatant was diluted to 75 μl in EHI5ZA (solid-phase enzyme-linked immunosorbent assay) buffer (containing RVZ with 0.5 96-m VBA, 0.05 95-m Tmeep-20) with or without the addition of 5 nM dadi or dad2 and incubated for 1 h at room temperature in an E-plate (MOMS). 95 μl of the mixture was transferred in parallel to tablets coated with the protein mixture. The tablet was gently shaken for 15 minutes and washed ten 60 times using РВ5-0.05 95 PMUEEP-20. Binding was quantified by adding horseradish peroxidase (HER)-conjugated anti-M13 antibody in ELISA buffer (1:2500) and incubating for 30 minutes at room temperature. Tablets were washed with RV5-0.05 95

Tmzheep-20 ten times. Then, 100 μl/well of the peroxidase substrate was added to the wells and incubated for 5 minutes at room temperature. The reaction was stopped by adding 100 μl of 0.1 M phosphoric acid (HzPOx) to each well and incubated for 5 minutes at room temperature. OO (optical density) for the yellow color in each well was determined using a standard tablet spectrophotometer for EGISA at 450 nM. Compared with the reduction of Oyuavonm ( 95) in the well with parental phage (100 95). Clones for which a decrease in OYulvonm ( 90 ) less than 50 95 was observed were selected for sequence analysis. Unique clones were selected for phage isolation to determine binding affinity (Phage IS2) against Udad1i or

Uad2 by comparison with the corresponding parental clones. Then, the clones with the most improved affinity were reformatted in human dSC1 for obtaining antibodies and further analysis of binding kinetics using ViAsoge and other IP migo or IP mimo assays.

Subsequent rounds of screening revealed antibodies specific for only one member of the Uhaddeid family of proteins, as determined by EG I5A. Antibody A bound human daddea1 and murine daddea1, but not daddea2 (Fig. 8; the sequence of the variable region of the heavy chain is shown in

ZEO I MO: 9, the sequence of the variable region of the light chain is shown in ZEO IU MO: 10).

In contrast, antibody B (the parent antibody of antibody B-3) bound human and mouse

Uadded2, but not daddeia1 (Fig. 8). C-1 binds to both daddea!1 and dhadded2 and served as a control. The sequences of the variable regions of the heavy chain and the light chain for antibody C-1 are shown in fig. 4.

Example 2. Antibody binding affinity and epitope mapping.

The binding affinity of anti-)adde4d! of phage antibodies was measured using surface plasmon resonance (SPR) using the ViAsogetm-3000 instrument.

Phage anti-Udded1/2 human IDS were captured on a CM5 sensor chip coated with murine anti-human DS antibodies to yield approximately 150 response units (RUs). For kinetic measurements, two-fold serial dilutions of human or mouse dad1/2 05 ЕСЕ1-4 (1.95 nM - 250 nM) were administered in PVT buffer (РВ5 with 0.05 95-m Tm'eep-20) at 25 C with

With a flow rate of 30 ml/minute. Association rates (Kol) and dissociation rates (Kon) were calculated using the Langmuir model of simple binding in a ratio of 171 (VIASOVEF Emaitsayop Zoiwage megbiop 3.2). The dissociation constant at equilibrium (Ka) was calculated as the ratio Kon/Cop.

Table 2 shows the binding constants for the binding of antibodies A, A-1, A-2, B and B-3 to purified human ZChaddei!, human dadded2 and mouse dadded2. The parental antibody specifically binds to human and mouse Dadde1. Affinity mature antibodies A-1 and A-2 bind to human and murine CHUaddei! with high affinity. Antibodies A, A-1, and A-2 do not bind to human or murine dadded2. In contrast, antibodies B and B-3 do not bind to human or murine Uaddea1. B-3 specifically binds to human and mouse dadded2.

Table 2

Summary table according to Viasoge

Kop Kok Kop Kok Kop Kok ome oyu mi me | bye | km | oh oh um

And | 23E04 |2LE-03|94E-08 No binding up to 5 mm! /-:

A-1| 8,304 |59E-05|I 7LELOI HER Г1111171С111111й1

A-2| 2,305 |7LE-O5| 30 ELOY 7777/1711 1111С11111 in No binding up to 0.5 μMI 2.5E-06b | 2.6E-0O3 | 1.0E-09 | 2.5E-06 | 2.6E-O3 | 1.0Е-09 вЗЙ 17717711 1758Е05 | 1.75E-04 | ZOETO

The sequences of the heavy chain and light chain variable regions for antibody A are shown in BEO IU MO: 9 and 10, respectively. The sequences of the heavy chain and light chain variable regions for antibody A-1 are shown in BEO IU MO: 17 and 18, respectively. The sequences of the variable regions of the heavy chain and the light chain for antibody A-2 are shown in ZEO IU

MO: 25 and 26, respectively. The sequences of the variable regions of the heavy chain and the light chain for antibody B-3 are shown in 5EBO IO MO: 41 and 42, respectively. The sequences of the heavy chain and light chain variable regions for antibody B are shown in Fig. 4.

Example 3. Anti-daddea antagonistic antibodies inhibit the daddea1-induced signaling pathway of ip miigo.

In order to determine whether anti-Uaddei antibodies could act as antagonists of the Chdaddea-induced Moisp signaling pathway, co-culture experiments were performed essentially as described in UMy et al., Maishge 464, 1052-1057 (April 15, 2010). MIN-ZTZ cells engineered to express Uhaddei1 as a Moses ligand were co-cultured with MIN-ZTZ cells that stably express MoisNP and which were transiently transfected to express a Moses-responsive reporter with firefly luciferase, TP-1 (12X C51 ), and a reporter, which is constitutively expressed, with luciferase from Kepia (rKI-SMU, Rgoteda). Strong signal

Moisp-reporter (firefly luciferase) was observed in co-culture (Fig. 12, induced 91 positive control). The expression of the reporter was reduced to the background level when the γ-secretase inhibitor was added to the co-culture, demonstrating MoIsp-dependent expression of the reporter construct. Data not shown.

Addition of increasing amounts (0.016-50 μg/ml) of anti-dUad antibody A-2 (sequences of variable regions of heavy chain and light chain with 5EO IU MO: 25 and 26, respectively) or

B-3 (sequences of the variable regions of the heavy chain and the light chain with 5EO IYUO MO: 41 and 42, respectively) resulted in a dose-dependent inhibition of reporter expression (Fig. 9).

The signaling pathway was induced by the daddeai! (Fig. 9A, dark gray bars) or daddea2 (Fig. 9B, light gray bars) and inhibition was determined as described above. Controls included cultures that were not stimulated with ligand and were not treated with antibody (Fig. 9A and B, untreated), that were not stimulated with ligand (Fig. 9A and B, unstimulated), were treated with 5-10 μg/ml isotype control antibody (Fig. 9A and B, ad) were stimulated with ligand, but not treated with antibody (Fig. 9A and B, stim./no AT), were treated with 5 µM gamma-secretase inhibitor, SART, or carrier for OART, OM50O.

Antibody A-2 inhibited Uhadded1-induced signal transduction, but not Daddea?2-induced signal transduction, in a dose-dependent manner (Fig. 9A). The IC for A-2 was between 2 and 10 μg/ml for daddea1 inhibition, while little or no inhibition of dadde2 was observed even at the highest concentration of 50 μg/ml. The results show that antibody A-2 is a selective antagonist of daddea!, that is, antibody A-2 inhibits dadde1-mediated

Zo signal transduction, but not Daddea2-mediated signal transduction. In contrast, antibody B-3 strongly inhibited dadded2-induced signaling at the lowest concentration tested, but did not inhibit that induced by Wadded! signaling at the highest concentration tested, thus proving that B-3 is a dhaddeia1-selective antagonist (Fig. 98).

Example 4. Effect of anti-Uaddea antibody on body weight.

As described above, gamma-secretase inhibitors and other Moisp receptor inhibitors cause weight loss and metaplasia of goblet cells of the intestine, which is undesirable for clinical use. In order to determine how the antibodies described in this document affect body weight and the condition of the intestines, mice were injected twice a week with anti-Chaddes!1 antibody A-2 (5-20 trK (mg of antibody per kg of mouse body weight), sequences of the variable regions of the heavy chain and the light chain with BEO IUO MO: 25 and 26, respectively), anti-Uadded2 antibody B-3 (5-20 trK, sequences of the variable regions of the heavy chain and light chain with 5EO IU

MO: 41 and 42, respectively), antibodies A-2 and B-3 together (5 trK each), anti-daddea1/2 antibody, which binds to daddea9! and daddea2 (C-1; 5-10 trK, the sequences of the variable regions of the heavy chain and the light chain are shown in Fig. 4), or control isotype anti-duo antibody (20 trK). An isotype control antibody was also used to bring the total antibody concentration in each dose to 20 trK. The total body weight of each mouse was determined before the first injection of antibodies and monitored until the 12th day of the study.

The average change in body weight is shown in fig. 10 as a percentage of the original body weight. Double inhibition of daddeid1!i and daddeid2 using anti-)addei 1/2 antibody C-1 or a combination

Uaddea1-specific antibody A-2 and daddea2-specific antibody B-3 led to rapid and significant weight loss (Fig. 10A). By day 4, some mice that received the anti-addei1/2 antibody

C-1, lost more than 5 95 of their body weight, and the weight loss progressed to almost 8-10 95 of their body weight on day 7 (Fig. 10A). Mice receiving A-2 and B-3 also lost weight rapidly, in some cases up to 179o on day 11 (Fig. 10A). In contrast, none of the Udaddea1-specific or Dadded2-specific antibodies alone caused weight loss over the course of the study at each of the 5 or 20 iprkK doses (Fig. 10A). The effect of the combination of anti-Uaddeai1 and anti-

U9added2 antibodies led to a decrease in food intake (Fig. 108), which correlated with the decrease in body weight observed (Fig. 10A) and suggested that a decrease in food intake may fully or partially explain the corresponding decrease in body weight.

Example 5. Anti-dUaddeid1 antagonistic antibodies inhibit the growth of human lung cancer cells ip mimo.

Saia-6 cells of the human non-small cell lung cancer line were transplanted subcutaneously into non-muscle naked mice from Nagiap. After the tumor volume reached approximately 200 cubic mm, mice were injected intraperitoneally (IP) twice a week (on days 0, 4, 7, 11, 14, and 18) with 20 trKc anti-d90 isotype control antibody (p -10) or anti-Uadded1 antibodies

A-2 (p-10; sequences of variable regions of heavy chain and light chain of ZEO IYUO MO: 25 and 26, respectively). The volume of the tumor in each mouse was measured with a caliper for another 19 days. The total body weight of each mouse was monitored throughout the study.

Tumors in mice that received anti-Uadded1 antibody were significantly reduced in volume relative to the volume of tumors in the control group (Fig. 11A). The effect of the anti-Udded1 antibody can be detected already on the 7th day after the introduction of the antibody (Fig. 11A). On day 18, the mean tumor volume in mice receiving the anti-Waddei1 antibody reached approximately 500 mm", whereas the mean tumor volume in control animals reached approximately 750 mm on day 18. No significant changes in body weight between the treatment and control groups (Fig. 118).

Example 6. Anti-Zaddea1 and anti-)Addeda2 antibodies inhibit the growth of human breast cancer cells.

MOA-MO-468 cells, a basal human breast cancer line, were transplanted into the mammary fat pad of SV-17 5СИО.б9 mice. After the volume of the tumor reached approximately 200 mm3, the mice were injected with IR of 30 trK anti-dO0 control isotype antibody (human isotype 901), control isotype antibody to ragweed antigen (mouse IdsS2a isotype), anti-UChadded! antibodies A-2 (sequences of the variable regions of the heavy chain and the light chain with 5EO IO MO: 25 and 26, respectively) in the framework of human YID9C1, anti-

Uaddeid1 antibody A-2 in the framework of mouse Idsg2a or anti-Dadded2 antibody B-3 (sequences of the variable regions of the heavy chain and light chain with 5EO IYUO MO: 41 and 42, respectively) in the framework of Y(DS1 human on days 0, 4, 7 , 12, 15, 18, 22, 25, 29, 32, 36, 43, 50, and 57. Tumor volume (y-axis) was measured with a caliper within 60 days after the first injection. Tumor volume for each group ( n-9 per group) were plotted using a linear mixed effects model (Figure 12A). Tumor volumes for each mouse in each group are shown in Figure 128.

From Example 7: anti-Uddaid1 antibodies are cleaved in the heavy chain

Antibodies A (sequences of the variable regions of the heavy chain and the light chain with BEO

IO MO: 9 and 10, respectively), A-1 (sequences of variable regions of heavy chain and light chain with 5ZEO IYU MO: 17 and 18, respectively) and A-2 (sequences of variable regions of heavy chain and light chain with ZEO IYU MO : 25 and 26, respectively) were analyzed by SDS-PAGE electrophoresis and spectrometry-mass spectrometry for the integrity of heavy and light chains. For SDS-PAGE electrophoresis analysis, each antibody sample was mixed in equal volumes with 2x Tris-glycine 5ZUO5 sample buffer (Momech, cat. Mo I/C2676) in the absence and presence of 10 mm OTT. The samples were heated at 95 "C for 5 minutes, and 2 μg of each sample was applied to 1 mm of a Momech 4-20 95 505-RACE gel (Momekh, cat. Mo ESb6O025). 10 μl of molecular weight standards, Magk 12, were also applied to the gel (Ipmigodep, cat. Mo 100006637). Electrophoresis was performed in their Tris-glycine DSN buffer for phoresis (Ipigodep, cat. Mo I! Сб2675-5) at a constant voltage of 2508, until the tracking dye reached the end of the gel. The gel was then stained with Coomassie dye (Ekhredeop IpziapiVine, cat. Mo. IZVII).

For mass spectrometric analysis, each antibody was diluted to a final concentration of 1 mg/ml in PB5. The pH value of the antibody was increased to 8.0 by adding 1:10 volume of 1.0 M Ttgi5 buffer,

pH 8.0. To restore the antibody, OTT was added to the solution to a final concentration of 10 mm. Then the sample was heated at a temperature of 37 "C for 15 minutes. Then the samples were applied to the column

RIAR-5 1000 angstroms, 8 μm, 2.1x50 mm (Aosdiepi, RI 1912-1802), heated to 80 "C, using an Adiepi 1200 HPLC system with subsequent electrospray ionization in a TOE I S/M5 system, Adiepi 6210.

The results of these analyzes are shown in Fig. 13. Electrophoresis in DSN-PAGE (Fig. 13A) showed that part of the heavy chain (HC) is split in each of the antibodies. Lanes corresponding to intact NS and light chain (LS), as well as carboxy-terminal and amino-terminal cleaved fragments of NS are marked to the right of the gel. A representative mass spectrometric analysis of antibody A-1 is shown in Fig. 13B. This analysis showed that the NA cleavage site is located between amino acids 100 and 5101 (sequential numbering, which corresponds to 596 and 597 numbering by

Kabatom) in SOMKZ, as schematically noted in the amino acid sequence of NS in fig. 13C with an arrow indicating the cleavage site. Similar analyzes showed that NA cleavage occurs in all tested preparations of these antibodies (including subsequent expression in two different cell types, CHO and 293), and that cleavage occurs regardless of the type of Es region of the antibody (human YDO1 or mouse Idsg).

Electrophoresis anti-Uuaddea! in DSN-PAAG was actually carried out as described above.

Instead of Coomassie staining, antibodies were transferred to the RMOE membrane (Ipmigodep, cat. Mo

IGS2002) using Vioya Moadshie's Xsseiya (Ipmigodep, cat. Me EI90O51) at a constant flow of 0.35 A. The membrane was stained with Coomassie blue B-250. Samples on the membrane were subjected to M-terminal sequence analysis using the Arriley Viosuziet5 Rgosize Zedcepseg 494 according to the principle of sequencing described in Milli, 1973, May. Eplutoi 27: 942-1010.

The sequencing results are shown in Fig. 14. This method confirmed that the cleavage site corresponded to that predicted by mass spectrometry, which is located between amino acids (100 and 5101 (sequential numbering), which corresponds to (396 and 597 in the numbering by

Kabat) in the sequence of NS.

Cleavage of the heavy chain of anti-addled1 antibodies A, A-1 and A-2 was unexpected. Analysis of the amino acid sequence associated with the cleavage site did not reveal any known protease cleavage sites. The cleavage mechanism remains unclear and is not evident from antibody sequences.

Example 8. Mutation 5101 in the heavy chain reduces cleavage of the heavy chain of anti-

Udaddey1 antibody how much cleavage was observed, anti-Udaddey11 antibody was unexpected and the mechanism unclear, it was not known whether changes in the antibody sequence could prevent cleavage while maintaining the affinity and efficacy of the antibody. In addition, it was not known which position in the antibody sequence must be changed to prevent cleavage. In order to determine whether cleavage of the antibody could be prevented by altering the heavy chain sequence, a series of amino acid substitutions were made at position 5101 of the heavy chain (sequential sequence numbering of the heavy chain variable region ZEO IU MO: 17, which corresponds to 597 in the Kabat numbering). Antibodies were expressed in mammalian cells and purified according to standard procedures. Cleavage was analyzed by SDS-PAGE electrophoresis as described in Example 7. The results are shown in Fig. 15. Amino acid substitutions at position 5101 significantly reduced or eliminated NA cleavage, although some cleavage was detected at

From mutation 5101H (Fig. 15, lane 5). These results were confirmed by mass spectrometry performed as described in Example 7.

In order to determine the effect of changes on binding to a purified fragment of the extracellular domain of the dad1 protein, the binding affinity of mutant A-1 antibodies was measured using

VIAsoge. Table C provides brief information on the fragmentation and binding affinity of

Uaddei1 for each of the mutant A-1 antibodies.

Table C

Fragmentation and affinity of binding to Udaddea1 of mutant antibodies A-1 01 Presence of NA fragmentation Binding to dad1 (ViAsoge)

Variants of MAT Mass spectrum DSN-PAGE Ka (1/Mes) | Ka (1/s) iv)

A-1

A-1

A-1

A-1

A-1

A-1

A-1

A-1 ethylene vet reeo ssshtloo0, eto Kk ' ' '

А-1 ве 111144 вех вен тео

A-1 byu yawns theo veteov

A-1 sells 00010000 ova vavyavov

A-1 will sell 0,000,000 new vehicles

A-1 mm with STO o

A-1 styuvyum 00001000 exactly |vvoya vvyavov

As shown in Table 3, changing the amino acid residue at position 101 reduces cleavage to an undetectable level, with the exception of 5101H. In addition, since the cleavage mechanism was unknown, the change at position 100, C100A was also investigated. The C100A mutant was still cleavable. See table 3. Surprisingly, despite the fact that these mutations were carried out in NME-NZ, mutant antibodies for 5101 retained the ability to bind daddea1.

Example 9: the effect of temperature and freeze-thaw cycles on the cleavage of the heavy chain of the anti-Uddeid1 antibody

In order to assess whether the cleavage of anti-)addea!1 antibodies is enhanced by incubation at an elevated temperature, different independent preparations of anti-Addea!1 antibodies A-1 (sequences of the variable regions of the heavy chain and light chain with 5EO IU MO: 17 and 18, respectively) and A-2 (sequences of the variable regions of the heavy chain and the light chain with 5EO IJOO MO: 25 and 26, respectively), as well as a control isotype antibody (not anti-Zaddea!1), incubated for 10 min at 70 or 95 " C. The degree of cleavage was assessed by standard SDS-PAGE electrophoresis and protein staining. The results are shown in Figure 16. Each of the anti-Udded1 antibody preparations was cleaved at 70°C, whereas the control antibody was not cleaved (Figure 16A). As shown in the table (Fig. 168), the degree of cleavage of anti-

Uaddea!1 antibodies probably or reproducibly did not change during incubation at 95 "C relative to 70 "C.

In order to assess whether freeze-thaw cycles lead to cleavage, anti-Udded1 antibody preparations, antibody A-1 (heavy chain and light chain variable region sequences from ZEO IU MO: 17 and 18, respectively) were subjected to multiple freeze-thaw cycles at -80 "C followed by thawing. 2 μg of each sample was then analyzed by SDS-PAGE electrophoresis under non-reducing (-0OTT) or reducing (OT) conditions (as indicated) and protein staining. The stained gel was visualized using a Viogai instrument SeIros Eazu Itadeg, and densitometric analysis was performed using the software of Viogai Itade I ar. The results of this experiment are shown in Fig. 17. E/1 refers to the original sample, and increasing numbers indicate the number of additional rounds of freeze-thaw cycles. each cycle, the A-1 antibody was frozen at -80 "C, and then thawed at room temperature. An aliquot was taken

Zo for electrophoresis in DSN-PAGE. Freeze/thaw was repeated two more times for a total of 3 freeze/thaw cycles, with aliquots taken after each thaw stage. The table (Fig. 178) shows the percentage of splitting in each condition.

The experiment showed that additional freeze-thaw rounds affected the degree of cleavage.

Example 10: Activity of A-1 and A-1 (51017) which blocks Uaddeai1, ip mygo

IP migo analysis of dad1-induced activity of the MoiSP reporter by co-cultivation was performed to measure the activity of A-1, which blocks dad1, (sequences of the variable regions of the heavy chain and light chain with ZEO IU MO: 17 and 18, respectively) and A-1 (51017 ) (sequences of the variable regions of the heavy chain and the light chain from ZEO IYUO MO: 33 and 34, respectively). SH87MO cells, which express high levels of Moisp2, were co-transfected with a Moisy-responsive reporter with firefly luciferase (ER), TR-1 (12X C5I), and a constitutively expressed reporter with Kepia luciferase (rEIG-SMU, Rgoteda ) to control transfection efficiency. See UMy ei ai.,, 2010, Maishge 464: 1052-1057. Anti-

Uadde1 antibody A-1 or A-1 (51017T), isotype control antibody, 5 μM SART (CaiIriospet), or control OM5O vehicle were added to ligand-expressing cells (MIN-ZTZ cells stably transfected with human Uadi or control without ligand) b hours after transfection. Luciferase activity was measured after 20 hours of co-cultivation (Rgoteda, Yutsai Siyu I isitegase kit). Typically, each condition was analyzed in quadruplicate, and values were expressed as relative luciferase units (firefly luciferase signal divided by the luciferase signal from Cephalonia) and plotted as a percentage of

Uad1-induced activity relative to control with antibodies against ragweed antigen.

The results of this experiment are shown in fig. 18. Firefly luciferase and Kepia luciferase (Fig. 188 C, respectively) were measured dose-dependently by standard methods, and the ratio of firefly luciferase and Kepia luciferase was plotted as a normalized measurement of Ad1-induced Moses activity (Fig. 18A). . The results show that both antibodies, A-1 and A-1 (51017), inhibit the Dad1-induced Moisp signaling pathway in a dose-dependent manner. See fig. 18A and B. Thus, A-1 (51017) retains the anti-Uaddea1 activity of the parent antibody that blocks A-1.

Example 11: activity of A-1 and A-1 (51017), which blocks daddea 1, ip mimo

To evaluate the activity of anti-Udaddea1 antibodies, which blocks Udaddea, i.p. mimo, the presence of cells

Clara and ciliated cells in the bronchiolar epithelium of the lungs of mice were measured after administration of control or anti-addei1 antibodies to mice. Eight-week-old female VAH B/s wild-type mice (three mice in each group) were injected with antibodies on day 0 (zero) as follows (all groups included an anti-Added2 antibody (B-3) to sensitize the bronchiolar epithelium to clearly detect the measured effects of anti-Zaddei1 activity): 1. Control 1X - isotype control (15 mg of antibody per kg of mouse body weight) and anti-Uad2 B-3 (15 mg/kg; sequences of variable regions of the heavy chain and light chain with 5EO IU MO: 41 and 42, respectively) 2. A-1 1X - anti-dad1 A-1 (15 mg/kg, sequences of variable regions of the heavy chain and light chain with BEO IU MO: 17 and 18, respectively) and anti-Uad2 B-3 (15 mg/kg) 3. A-1 5X - anti-Uadi A-1 (7.5 mg/kg) t anti-dad2 B-3 (15 mg/kg) 4. A-1 25X - anti-dad1 A-1 (3.75 mg/kg) t anti-dad2 B-3 (15 mg/kg) 5. A-1-5101T 2X - anti-Uadi A-1(5101T) (30 mg/kg; sequences of variable regions heavy chain and light chain with BEO IU MO: 33 and 34, respectively) t anti-Chad2 B-3 (15 mg/kg) 6. A-1-51011 1X - anti-Uada1 A-1 (510 1T) (15 mg/kg) t anti-Uad2 B-3 (15 mg/kg)

Zo 7. A-1-51011 5X - anti-Dadi A-1(51017) (7.5 mg/kg) and anti-Uad2 B-3 (15mg/kg) 8. A-1-5101T 25X - anti - Uadi A-1 (51017) (3.75 mg/kg) and anti-Uad2 B-3 (15 mg/kg).

On day 5, lungs were harvested, inflated, fixed, and stained for immunofluorescence (IBR) as follows. The lungs were inflated using 4 90-th REA in RV5. The entire lung was transferred to 10 95 neutral buffered formalin (NBU) and fixed overnight at room temperature. The fixed lungs were transferred to 70% ethanol for at least 24 hours. Lungs were immersed in paraffin and sections of 5 µm were made. Immunofluorescent staining of ciliated cells and Clara cells was performed as follows. Slides were deparaffinized, and antigens were revealed by boiling the slides in citrate buffer (OaKko, cat. Mo 51700) in a pressure cooker for 15 minutes at 125 °C. The slides were quickly washed in 2X RVB5B and then permeabilized with 0.2 95-m Tpyop -X100 in PB5 for 45 minutes or 3 times for 15 minutes. Sections were blocked in 5 95 EB5/2 95 WBA for 1 hour. Sections were then incubated with goat anti-CC10 antibody (1:1000) and mouse anti-acetylated alpha-tubulin antibody ( 1:200) in blocking buffer for 2-3 hours or overnight. Sections were washed with RVZ 3 times for 15 minutes. Sections were incubated with secondary antibodies for 1 hour (secondary antibodies from

Ipmigodep AiIeha RiIshog was diluted in a ratio of 1:1000), and then washed twice with RV5 for 15 minutes each. Nuclei were stained with BARI (0.5 μg/ml) for 15 minutes. The slides were then washed

RVZ5 twice for 15 minutes and mounted under a cover glass.

The results of this experiment are shown in fig. 19. Blocking of Uaddea signaling pathways and

Uadded2 leads to an increase in the number of ciliated cells (indicated by immunofluorescent detection of alpha-tubulin in the red channel) and a decrease in the number of Clara cells (indicated by immunofluorescent detection of CC10 in the green channel) in mouse bronchiolar epithelium.

Simultaneous blocking of daddea!1 and dadde2 leads to an almost complete loss of Clara cells, so that as a result the epithelium consists mainly of ciliated cells (stained in red, see "A-1, 1X" and "A-1-5101T, 2X" in Fig. 19). Both antibodies, A-1 and AT (51017), inhibited the dadd1-induced signaling pathway of Moses ip mimo in a dose-dependent manner. So,

A-1 (51017) retains the anti-Added1 blocking activity of the parent antibody A-1 ip mimo.

Example 12: anti-Udded1 antibodies A-1 and A-1 (5101) inhibit the growth of liver cancer tumors ip mimo

Human liver cancer tumor, ГИМЖ78 (Sepapadezidp, China), was grown as a subcutaneous xenograft in the VAI B-z line of athymic immunodeficient mice. When the tumors grew to a size of 150-200 mm3, the mice were divided into seven treatment groups of ten mice in each group, which were injected once a week (with the exception of group 5, where the injection was carried out once every three weeks) at the indicated dose (mg antibody per kg of mouse body weight) the indicated antibodies (antibody A-1 (51017), which has sequences of heavy chain and light chain with BEO

IO MO: 51 and 53, respectively, "A-1-OAMO (non-effector)", which has heavy and light chain sequences with BEO IO MO: 52 and 53, respectively, and antibody A-1, which has sequences of heavy chain and light chain with BEO IU MO: 81 and 53, respectively). See fig. 208. The volume of tumors was estimated based on the results of caliper measurements (length, width, height)/g).

In fig. 20A shows the 1st ME graph (linear mixed effects) of tumor volume in each treatment group over the course of the study. In fig. 208 combined growth statistics, group characteristics and treatment regimens. Anti-Daddyd1 antibodies A-1 and AT (5101T) significantly inhibited the growth of liver cancer and mimo; multiple RCs (partial responses) were observed for each of the anti-Uaddei1 antibodies.

Similarly, none of the groups receiving anti-Uaddei1 antibodies experienced a doubling of tumor volume during the 44 days of the study, while the time to tumor doubling (TTR 2X) was 18.5 days in the control group. See fig. 208. Percent inhibition of tumor growth (956 IU, where the "lower" and "upper" values refer to the minimum and maximum measurements of 95 IU, respectively, for individual animals in each group) as a function of the area under the curve per day (AUC/day), compared to the control group, was dependent on the dose of anti-Uaddea1 A-1-5101T according to the inhibition of tumor growth, which reflects the degree of inhibition of Daddea!1.

Similarly, inhibition of tumor growth was similar when using A-1 or A-1 (51017). You can compare, for example, groups C and 7, fig. 208. Inhibition of tumor growth was independent of the effector function of the antibody, because the M2970c heavy chain mutant form of A-1, which lacks effector functions, suppressed tumor growth as effectively as A-1. You can compare groups 6 and 7, fig. 208.

In fig. 21A shows the 1st ME plot (linear mixed effects) of mouse body weight versus dynamics for the mice shown in FIG. 20. In fig. 20B shows various parameters of body weight for the treatment groups, including the 95 change in body weight on the last day of the study ( 95 W on the last day), the maximum change (in 95) in body weight (max 95 W), the day when the maximum change in body weight occurred (day max. 956 W) and (AOS/day (lower, upper value)). Body weight graphs for groups

Treatments, including the control group, were statistically indistinguishable, indicating that treatment with anti-ADDEID1 antibodies was well tolerated.

Example 13: Blockade of Waddei!1 inhibits goblet cell metaplasia ip mimo

After a 35-day sensitization period with intraperitoneally administered ovalbumin, mice were aerosolized with ovalbumin for 7 days, then sacrificed and analyzed for goblet cell counts. Mice received a control antibody, anti-Added1 antibody A-2 (from ES from mouse Idsg), anti-Added2 antibody B-3 (from ES from mouse

Ids2a) or a combination of anti-Uadded1 and anti-Uadded2 antibodies 24 hours and 96 hours after the first aerosol administration of the allergen.

In fig. 23A shows staining with periodic acid - Schiff's reagent of pulmonary airways in mice that received anti-Uaddea1, anti-Uaddea2, a combination of anti-

Uadded1i and anti-Uadded2 or control antibody. In fig. 238 shows the determination of the number of goblet cells in the airways of groups that received different treatments. A large number of goblet cells is observed in the control and anti-Wadded2 groups. A few goblet cells were present in the anti-Uadde1 group and almost no goblet cells were detected in the anti-dUadd1 and anti-Uadd2 group. In fig. 23C is the indicator of inflammation, assessed by NaE staining (hematoxylin/eosin). Treatment with dadded-1 or -2 blocking antibodies does not affect inflammation in the lungs.

The Uaddea1-induced Moisp signaling pathway shifts airway cell differentiation from differentiation into ciliated cells to differentiation into secretory cells (including goblet cells). Signal path dudded! is important for maintaining secretory cell differentiation, and inhibition of the Daddea1 signaling pathway prevents goblet cell metaplasia. The authors of this invention also showed that the transformation of Clara cells into cilia is direct and not related to cell division (data not shown). Goblet cells will form from Clara cells in the lungs. This transdifferentiation of one type of cell into another occurs in the lungs of adults and is distinct from the choice of a cellular differentiation pathway that involves the distribution of progenitor cells, for example, after injury or during development. Goblet cell metaplasia, or excess mucus, is a feature of a number of airway diseases, such as asthma, cystic fibrosis, COPD, and Barrett's esophagus. These results of inhibition of the daddea-60 signaling pathway provide a basis for therapeutic applications, including the use of Uhaddeid1 or dadde2 inhibitors to prevent or reverse goblet cell metaplasia and to treat conditions characterized by excess mucus, such as airway diseases (e.g., asthma, COPD , cystic fibrosis) and Barrett's esophagus.

Example 14: binding specificity of anti-added1 and anti-Uadded2 antibodies

Antibodies A-2 (Fig. 24, left panel) and C-1 (Fig. 24, right panel) were tested for binding to recombinant purified Moisp ligands - human daddea!1 (pOdad-1), human Chuaddeag2 ( pPdad-2), mouse daddea2 (tuad-2), human Oena-yike 1 (PO I1), mouse Oeka-yike 1 (p0Y11) and human Oeka-yKe 4 (p01I14), using a standard solid-phase enzyme-linked immunosorbent assay (EGIBA ). 1 μg/ml Moisp ligand (as indicated) in РВ5, pH 7.4, was applied to EGISA plates (Mips Mahizogr) at 40 °C overnight. Plates were blocked with casein in RVZ (Riegse) for one hour at room temperature. Consecutive

Three-fold dilutions of IdsC antibodies (as indicated) in RVZT buffer (RVT buffer (РВ5ш0.05 95 (vol./06.) Tzhsheep-20) with 0.5 95 (wt./vol.) B5A) were added to tablets and incubated for one hour at room temperature. The plates were then washed with РВ5T, and bound antibodies were detected using peroxidase-conjugated goat IdS antibodies specific for

Human Bar (Zidta). TMB substrate (3,3',5,5'-tetramethylbenzidine) was used, and absorbance at 630 nm was determined using a standard tablet spectrophotometer for EGI5A. The absorbance was plotted against the concentration of dv using Kaieiidastari (Zupegda Zoymage). In fig. 24 shows the results, where Avzo on the y-axis represents the degree of binding.

Antibody A-2 bound human and mouse daddea/1, but did not bind human dadde2, mouse dadde2, human 01, mouse 01, human 01 4, or mouse OP 4 (Fig. 24, left panel). Antibody C-1 bound human and mouse dadde1, human and mouse 0 1, human and mouse dadded2, but did not bind human or mouse 01 1 4 (Fig. 24, right panel).

Binding affinities and rate constants for antibodies were measured by surface plasmon resonance (SPR) using a ViIAsogeti-T200 instrument.

Antibodies to human IDS1 were captured on a CM5 sensor chip coated with murine anti-human IDS antibodies until approximately 150 response units (RU) were reached. To measure

For kinetics or affinity, four-fold serial dilutions of human Daddea!, mouse Daddea, human CHUaddei2, mouse CHUaddei2, human 011, mouse 0111, human OGI 4, mouse 0G4, and rat Daddea1 were injected in HB5Z-T buffer (0.01 M NERES, pH 7.4, 0.15 M mass, 0.05 95 vol./o0 vol. Bipassiapi P2O, SE Neaxage) at 25 "C with a flow rate of 30 ml/min.

Ligand fragments were fragments of Y5I-ESIE1-4, with the exception of rat daddea!1, which was purchased from KU Bouziet5. For kinetic analysis, the rate of association (Kol) and the rate of dissociation (Kozh) were calculated using the Langmuir model of simple one-to-one binding (ViAsoge T200 EmaiYitsayop bBoitmage megviop 2.0). The equilibrium dissociation constant (Ka) was calculated as the ratio Con/Cop. For analysis Ka affinities were calculated using the stationary affinity model (ViIAsoge T200 EmaInayop bZoimage megsiop 2.0).

Table C shows the binding constants for antibodies A-2, B-3, C-1, A-1, and A-15101T that bind to purified human Zaddei1, mouse Uaddei1, human Dadded2, mouse

Wadded2, human 0/1, mouse 0/1, human 014, mouse 0114 and/or rat

Udaddei1. HB - not detected, NT - not tested. Antibodies A-2, A-1 and A-1-51017T.M5 (antibody A-1-25101 with M29705 mutation) specifically binds to human and mouse daddeid1 with high affinity.

Antibodies A-1 and A-1-5101T.M0 also bind to rat ChUaddei! with high affinity.

Antibody B-3 specifically binds to human and mouse UChadd4y2 with high affinity.

C-1 antibody specifically binds to human and mouse Daddeai!1 and Khdadde2. Antibodies B-3 and C-1, but not antibody A-2, showed some binding to human and murine 011. None of the antibodies tested bound to human or murine Oi 4.

Table C

Binding constants for anti-Zaddea antibodies of our shilly skh write about oleoresyu tyu Hayko kov. loop

Continuation of Table Z

Binding constants for anti-Uaddea antibodies

GAY AOTTMaSSSSSSSS 1111110 Keai(/Mee) | Kok(is) | Ke(M) | Koa(1/Messier) | Koi(/s) | Ka(M)

Example 15: pharmacokinetics of anti-Uaddea1 antibody A-1-51017T

The pharmacokinetic profile of the anti-Uaddy antibody A-1-51011 after a single intravenous injection at a dosage of 1, 10, and 100 mg/kg was evaluated in female athymic mice

Vai!B/s (Snapez Vimeg I abogaitiev, NoiIiviei, SA). Mice were 5-8 weeks old and weighed about 17.3-21.8 g. Serum samples were collected, and antibody concentrations were analyzed by solid-phase enzyme-linked immunosorbent assay (ELISA) for binding specificity. Tablets for

ELISA to assess the specificity of binding was covered with the extracellular domain of Зас1-histidine, and detection was performed using goat antibodies against human ES. The sensitivity of the assay was below the standard value of 6.25 ng/ml. Pharmacokinetic parameters were estimated using a non-compartmental model using Rioepitm UUipMopiiptF (m.6.3;

RPpagzidni Sogrogayop; Moshipiaip Miem, SA). All pharmacokinetic analyzes were based on the original pool of data from individual animals.

A greater than dose-proportional increase in exposure was observed after intravenous administration of the anti-)addei1 antibody A-1-51011 in the dosage range from 1 to 100 mg/kg, indicating a mechanism of target-mediated clearance of the antibody (Fig. 25 and Table 4). .

Clearance values range from approximately 13 to 75 ml/day/kg.

Table 4

Pharmacokinetic properties of anti-Uaddey1 antibody A-1-51017T

Although the present invention has been described in detail by way of illustration and example for purposes of clarity of understanding, the description and examples should not be construed as limiting the scope of the present invention.

The disclosure of all patent and scientific literature cited herein is expressly incorporated by reference in its entirety.

Table 1 Uad1i of a person MABZRATNON5Z SARI BIG AG ISAI VAKMSO AZOOBKEI B.

ZMOoMUMaeGOo mamMmoSasAVM RESAKSTAOE SOTUMEKMSI K

EMO5AUMTASO ROSERAZIAZTR MISSMTEMIK AZS, MOVMNI

MIGREBEAM/RA UT MEAMO 554 OTMOROB PEKAZNISM

IMRZVOUMOTI. KOMTOYAaMANEE MOIVUTOR UUaBasmMkEs

ARAOOERIN ASROMOamKTO MESUMUMORESM VAISNOSS5R knazskiRIr sSASOMamoa uSOokSIRNRa sSMnaTai(smmMmERM/

OSI SETMUUSsO OY SOKOI MS anorsi Mas to5MTaROKU

OS5SRESUBOa RMSOEIAENAS AND 5ORSNMNYa5 SKETOI SBES

ES5ROMTART SZTMIOYUSZR MMSoZNOOZTSO BI UMavgkKoMUs

RROMUTOaKTtTSO GOAMESEAKR SUMAKZSKMI IAZUMSOSI R

SUUMOSOMSOIM IMOSI SOSOM OABSVOI Ma MASISRRIMA

SONSEVOIOE SABMRSI Masi NSOMEIIMARO SI SRERTOEBYM

GSsOGOHIOMSE RMRSOMYALOS UMAVAZOMESK SREOMESKMS

ZNI CONSEATT RSEMIOZSTM AMAZMOTRES UVMIZZMUSSO

RNOKSKZOVA ASKETSOoSMKA ETATUUSNEMI MOSEZMRSVM aa7atsIiraumMme ukSSISBOSME SAMSETMIMO S5BOMRONYUMYaS tTOOgUMOogM SoOSkKMahmkak tonZNOZOSO EATSOMMOSTO

UreEarAEXM SRYaSUeaTTOo MIAAVM5ZZSOYI R MRSNMOS TOMU

MMaeEBZETSMO KESM/ESRISA OMTMOSZRNR SUMZYTSura

ROMMUMASESAR SEASROSVIM IMESO5OROSA ESATOSMOBIM

SUASMSRRRIEN BSAKSOEMUza VARSITMa5MI ROSAKMOVBOS

MTSOSI MOVI ASZKUMSOIRA RUSSIA NKaN5ZE SRBZIAyuOBSIRI

GOBOSEMNRO TaMOaeESAB5Z GORUKTKST5 OBUMOOMSAM

TETEMKEMM 5RY TTENIS 5EI MI MIK MUZAEEEM5IMI ASERRBRBZAMM

EINMAIZAEV IVNORIMRIKE ITOKIOI M5 KAROaMZIPTA AMAEMAMOVA

R EKZHMATORIM RIA MEDIA TMA MSS MTAEM ALL VKAVKROAa

ZNTITNZABEOM TTMIMUVEOI M OIKMRIEKNOI AMTURIKOME

MKMZKMZKIV TNMZEMEEEVO MOKNOOKAVE AKORAMTI MO

VEEKRRMatTR TKNRMMTMKO OMAOGEZAOBZ I MAMEMIM 2 Uad1i mice MAZRATA!SAR SARI BI GAI ISAI VAKMSO AZOOBKEII B.

ZMOoMUMayegOo maMmoSaaMAM RESAKSTAOE SOTUEKMSI K

EMO5AUMTASO ROSERAZIAZTR MISSMTEMIK AZS, MOVMNI

MGREBEAM/RA SALES MEAMO 554 OTIOROB PEKAZNIZOM

IMRZVOMOTI KOMTOIai!ANEE MOTIVUTOVON UMaRasmmMmkEs

ARAOOERINU ASVOMOamKTO MESMUMOaROSM KAISNOSSVR knazski Ra sSASOMamoai hSOoksSIRNRa SUNaTtToOMERM

OSI SETMUSsSOYA SO SSOOKO MS atnoORSI Ma ToZMTaROKU

OSBSRESUBO RMSOBIAENAS AND 5ORSNMNOZ SKETZBOBES

ESBZROMTOART S5TMIUOS5R MMSOZNOSTSO PI UMagcosmMs

RROM/TaKTtSO GOAMESEAKR SUMAVZSKMI IAUMSOSI R

SUUMaIaomesrIM IMOSI SOSOM OVABSVOI UMO MASISRREMA

SONSEVOIOE SABMROI MasNSOMEIMABO SI SRTagM

GSsOGOI0MSE RMRSOMYaAOS UMAABOMESK SREOUESKMS

ZNI KONSATT TSEMIOZSTM AMABMOTRES MAMIZZMUSO

РНОКОКБОБаа АККЕТсОоСМКа еТатисСНЕМИ МOSEЗМРОКМ satSiramММ5 УкСИСВраТмЕ sСАНСЕММIMO SBOMRONUSO tovogUMOogM SOSKMamkak tonzNoOBOSO EATSMMOSto

MOEMOTEKSM SROSMBatTTtOo MANMZZSOYI R MRSNMAS VOL

UMARZETSMO KESMEARIST OMTMOS5RNR SUMZITtOSUra

OMUMUUVASESAR SEASROSVIM IMESOZZROA GSATSMOBYM

SMOSISRRON 5BSAKSNEMBYa NZSITMOa MI HOPAK OBOS

MTSOSI MAM ASZKUMUSOIRA RSVI NKZNME SRBSIOZSIRM

HOROSEMARO TaMayesSnyoz AND ORUKTKSTZ OBUMOOMSAM

ITETEMKEMM 5RSS-TTENIS 5BEI AMI MIK MUBAYEMBIMI ASSERBI BAMM

BINMAIZAEO INOVSYMRUKE ITOKITOY M KAROaMZBA AMAEMAMOVA

RI. ZHMATORIM RIYA ZBMISTMA MMSI MTAYEM MUSUVKAVKRB

ZNITNZAREOM TTMMMAEOII M OIKMRIEKNOYA AMTURIKOME

MKMZKMKIV TNYAZEMEEVO MOKNOOKMAE AKORMUMTI MO

VEEKARBITR TKNRMUUTMKO OMA EBAOZ AND MAMEMIM

From Human Uad2 |MAAOSVavViR AVS ASM/ MOADAVRMOIUE EGO ZAGAMM

Has zaASo raravttnAsa asanoRESOTU MAMSI KEMOA

KMTRTaRSZU SNOATRMI as MZEMI RRASA ASOVAVANAN aaroorROIM MIRRORGAM/RA BETYMEAM/O MOMOTTRMEE

PLEVAMZNAS MIMREOAMUK IGNEZINMANI. EGOIAUASOE

MUUZATSMKE SARAMORGROAN UTSPROMAMKKA SMOSUUMIAKES

KEAUSKOSSM GI. NnasasturRa ESASZUSUMOS VESOESMURUR aSUNazsmMER MOSMSETMUa SP SOKOI MM SaZNNROSTMOIa

STSIMAEROO MASTOROSU5 SAMSEKAENA STZMRSAMOS

ZSNEMRBZARE SNSRBOMUZAR TSAI OI0ESA BMRSAASYSTO

MROMRAGESI SREOMUMAATSO OY YUAMESESK OF RUSSIA MAYEZSKM

PasmUsosI ROMUKOIIMSNI M/MOSNOOSO NOI, TOKO MM vMOSUSReASE SYAVANSEGENO ESABBRONZO SI SEP ASK

NSNSROSEZA RI SEMOMOI S ERBERSAMSOAV SUMI eSOMUS

ASROVROYAKM SZMRVERSRO SASVMIRIASO Brasromrot

AABSUSIYARNOa ASUBOROSME ZSISOBageta TUSNEMISOS

HaORSAMASstT SIOEMOAENS ESRBOM/ESBY SOTMRMOSI R

ORONZNAVVSM AND MMOGEMSAS OBSUUKOaKkKTton 5VEROSOAHT

SsemMmaatoUr5 aOTEA!ASASRR SMU/KOaZTSAMA KMZZSOY RMRO

UumastoUsvBa ABEZSISNOS MESATSTNMT MOSMRI RSUM

SaISMramMM EAVSESAROBA SROSVIMIOE SOBZRSAMIaA

TOMOBIMOUA S5SRRaVASR VSOEMISRIV BSMUZAITRER nNazBUMmmMEOosSM SAS rOaANO SZKUMSOMKR SP ASOREAIH.

ZAOSRI OVNS GEKARSOSI IN RRSEAMSESO AEBERRZTROI.

RAZanNigOMMo AVT NEMNO NUROSTTMaA ISI RA

TAAMANONVII M''SOVAZZO ABAMEMAM5E ZRANOYI ROB

POSAANA!IM AAITONOIMO'Z AND GAMTEMKM ETUMTOSSOZ5T

SG GMRMI SOA EZMILMI ASUM I SMMUMUTAKAA KEVENZNI RA

EEBAMMOMAR AND MRIVMRIEEEA ROSNKOMI MO SKMETRRRAN

AREAGRORAS NAAMAEOEEEO EI JAVA eEOB AND EAEKRI ZNK

ETKOREV5ROEa AVRANUABORK MOMVAMABIM EANUASKE

4 Uad2 mice MAANSUOVI R AV MI S MOATARMOME EGOI ZASAMM

Has zaASo raravttnAa asSaVvoESOTU MAMSI KEMOA

KMTRTaRSBZU SUSATRMI SO MEM RRASA ASOVAVANZN

TASHONRSIM MIRREOBAM/RA ET MEAM/O UMOMOTTROEE

PLEVAMZNAS MIMREOAMUK IGNEZINMANI. EGOIAUASOE

MUUZATSMKE SARAMORGROAN UTSPROMAMKKA SMOSUUMIAKES

KEAUSKOSSM GI. NNIA1sstura ESASZUSMO KESOESMRUR asUNNazsmMER MUNSOSETMUUsS SP SOKOI MM SaZNNROUMYa

STSIMAEROSO MI SASROSMI SKMSEVAENA SABMRSAMOS

ZSNEMRBZARE SNSRBOMUZAR TSAI OI0ESA BMRSAASYSTO

MROMRAGESI SREOMUMAATSO OY YUAMESESK OF RUSSIA MAYEZSKM

PasmUsSosi ROMKOSIMSOI MIMOSNOIDYUOSO NOITOKOI MM vUOSURreASE SYAVANSEGEMO KSABZRONNO SISEPVI MOSS

ASNOSRNAI ZO I NSEMOMO S ERBRSI MEAV SUM eSrMUS

ASREORSOaKM S5MRAOTSRO SASAMIVOSOYA READOZAANIOM

ARZOISSYARNOa NSB ROSME 5SISOVAgheTTa TUSNEMIOOYUOS

MaoRSAMaat SsITEMOZEVNS GSRBZOM Ba! SOIMRMOSI R RORONZNAVVSSM AND MMOGHEMSAS OBSUMUKOACKKTTON ZAEROSPAMHT

SszmMaatoUry aOtTEASASRR SUUKOaZTSTIA KMZ5ZSMRMRO mchmastoUaza rgheSISNOS MESATSTNMT MOSMRI RSUM

SaISMramMM EAVSESAROBA SROSVIMIOE SOBZRSAMIaA

TOMOBIMEUA S5SRROaVNBOR VSOEMMIETA RSM/ZNOam5ER nazaUumMEorsmmM ZsvOSI early s5kMMUSSOamMkR SI Zaorbor

ZAOSRROSOS OEKAMOOSIO RRSEMM/SEST AEERI RROTR

COOPERATIVE OM MSAVI TI VEM AVROMROSTTM SAISZaitvAYI.

RATAAAANOYA PO SOVA BSAZAMEMAM 5EZRANOY RO

ЗЗПОЗАТАНА ИМАИИТОВим ЗБ AMTEM KMETUUMOS5

For MRMIS 5MEZMI UM AS MUMISUUM TAK AVKENEVZNI.

RAOEZTMMOMU ARY MRIAMRI EVNRSSZOG ST SYNKO MOSS

KMETRRRAVA SEAI RORASN SASSOSEEOEBOE EI ZNYArYarZR

EAEKRIZNKE TKORBOVI SA RASM/ARERKM OMAAUNOZTKO MAVASVE

Mouse dad1- | AHSUREGE and HOMMMMMOMMSSatsM of Vaurastt Ri-Jeag1-4 Reptour and Scomosamt Sorsvroazis TMSMTEM (mouse dad1- Im kabnammoam vimsrebeam rhimomotan rhmotymotyar antigen)

SMKAISNOSO 5RKNOZSKI R CHYSASOMSUO AND MSOKSIRN

REASUNATSME RMOSI SETMUU BOI SOKOM MSatTNoORSI M vato5MTaRO KMOS5SRESMU BORMSEIIIAEN ASI BORSNMA eZSKETOAE ESES5ROMTA RTOZTMIOOE SI MRASZON NNNNN

Human dad1-| OREG EI ZMO MUMayegomamm sbasAVMROO AKSTARESOT rI-eag1-4 URKMSGKEMO ZAMTAaaRSV hOBIaZTRMIS OMTEMI KAZANA (human SMOAMAIMI R EZEAM/RAZMT GG MEAMOBZM OTMOROBIE

Uadi antigen). | KABN5SMIMR ZVOUOTI KOM TOMANEREMOI NUTSrOUUMHO gasMkESSARA OSRRaNMASO OMEMKTOMES MIMO RESMVAAI spoasSzRKNOa SK arsSOo Mamo MSoKk SIRNSUNY

ISMERTMOSI S ETMUUSOSOI SO KO MUSATtno ROS MaatosvmM tTaROKMOS5OS RESBUBORMSE IAENASI BOR SNMNOSSKET

ZI SRESESVR SUuUTaRTOBTM ro 7 Mouse dadag- | AS YAZMOMRE GO ZAG AMUM SEP ZaASso apravtTtvAsOo rI-eag1-4 SavrESOTUM VMS KEMOAK MTRTaRSVZMUS MATRMI SHOM (mouse Dad- | «ZEM RRASAA SOVNAVANZAT SONOYURIA MM IRREOGAM/RAZ antigen) ETYMEAM/OM OMOTTROEEI GPEVMUMZNASM IMREOVUUKBI

NEZONMANIG EE GOIVMASOEM MUZATSOMKES AVRAMOGRYANU tTEROMAKAS MOOMUMOAKESK EAUSKOS, SMI. And NaaSstTUROE

SASBUSMOSOK ESOESURUROa SMNOZSMERM NSOSETMUU OS gl soKkoi Mys a5NNROUMiaIAs TSIMAEROOM AND SASROIMI S

KMSEVAENAS ABMRSAMOSYA SNEMRBORES NSRBOM/MORT

SAI OI0EEra ГМРАСЗИННННННН

Human Shdad2-| AVRMOMREEGO AND ZA AMUMOE GI 5SaSASSrar avttvaasasSa 0О5I-ЕСЕ1-4 NOESOTUMUVM SI KEMOAKMT RTARSVMOaNnaY ATRMI SM (human MI RRASADOO VAVAVANASY OBRII MMIR EOBGAM/RABET

Uadg2-antigen). PPMEAM/OM OM OTTRMEEKI EVMZ5NASMIM REOSRMMUUK5I NO

ZONMANI EGO IVUVVSOEMUM BATOMKESAR VMOeROYAaNMTo rOMamMkASMO SMUMOaKESKEA USKOSSMI NN SaSTUROESVA

S5USMOOaVES SESURURASMU NaZSMERMOS MSETMUM SO.

SSOOKOI MMSa5 NNRSTMYaSTO IMAERSOMAS TSROSUBYAVM

SEKAENASTO MRSAMYS5SN EMROSEBGESNO ROOSM5OaRTSA

IOI0EERaYi M RNDaBSINNNNNi N

Variable EMOY MEBOSIE AND MORISBI VI 5SAABOETE5 MMOINMUUVOA area ROaKagEMMOaMm ITROSamMtTOM AOBUKOVETI BAOTOKMTAU heavy GOMM5I VAEO TAMUUUSAVAS BM/gAMMSOST I MTU55 chain of antibodies A

Variable IOMTO5RBB5 AND BABMOaOVMT ITSVABOYUM5 TAMAMUMOOKR region of the light OKARKI IM5 ABERY U5OaMRO VEZOa5Oa5aITtO ETI TI OR chain EOEBATUMSOO 5BMUTTRRTESO aaTKMEiK antibody A 11 Hypervaria- sSETTEZMMain white area 1 of the heavy chain of antibody A

NMUVv-NI antibodies A antibodies A 14 Hypervaria- VABOVUZTAMA white area 1 of the light chain of antibodies A

НМВ-11 антитіла А антитіла А 17 Варіабельна ЕМОЇ МЕБОСІЄ І МОРИСБІ ВІ 5СААБОЄТЕ5 ММОІНМУУВОА область РОаКагЕММОаМм ІТРОСамМтТОМ АОБУКОВЕТІ БАОТОКМТАУ важкого ГОММ5І ВАЕО ТАМУУУСАНАС 5І ЕАММ/СОСТ І УТУ55 ланцюга антитіла А-1 18 Варіабельна ІОМТО5РББ5 І БАБМОаОВМТ ІТСВАБОЮМ5 ТАМАМУМООКР область легкого ОКАРКІ ІМ5 АБЕРЇ У5ОаМРО ВЕЗОа5Оа5аИТтО ETI TI OR chain EOEBATUMSOO MUTTATTERSO aaTKMEIK antibodies A-1 antibodies A-1 antibodies A-1 antibodies A-1 antibodies A-1 antibodies A-1 antibodies A-1

Варіабельна ЕМОЇ МЕБОСІЄ І МОРИСБІ ВІ 5СААБОЄТЕ5 ММОІНМУУВОА область РОаКагЕМУМУсаМм 1теамасУуомМ АОБУКОаВЕТІ БАОТО5КМТАУ важкого ГОММ5І ВАЕО ТАМУУУСАВАС БМ/гАММУСОСсТ І МТУ55 ланцюга антитіла А-2 26 Варіабельна ІОМТО5РББ5 І БАБМОаОВМТ ІТСВАБОЮМ5 ТАМАМУМООКР область легкого ОКАРКІ ІМ5 АБЕРЇ У5ОаМРО ВЕЗОа5Оа5аИТтО ЕТІ ТІ ОР ланцюга ЕОЕБАТУМСОО 5БМУТТРРТЕСО ааТКМЕїК антитіла А -2 antibodies A-2 antibodies A-2 antibodies A-2 antibodies A-2 antibodies A-2 antibodies A-2

ЗЗ Варіабельна ЕМОЇ МЕБОСІЄ І МОРИСБІ ВІ 5СААБОЄТЕ5 ММОІНМУУВОА область РОаКагЕММОаМм ІТРОСамМтТОМ АОБУКОВЕТІ БАОТОКМТАУ важкого ГОММ5І ВАЕО ТАМУУУСАНАС ТІ ЕАММУСОСТ І МТУ ланцюга антитіла А-1 5101Т 34 Варіабельна ІОМТО5РББ5 І БАБМОаОВМТ ІТСВАБОЮМ5 ТАМАМУМООКР область легкого ОКАРКІ ІМ5 АБЕРЇ У5ОаМРО ВЕЗОа5Оа5аИТтО ЕТІ ТІ ОР ланцюга ЕОЕБАТУМСОО МУТТАТТЕРСО ааТКМЕІК антитіла A-1 5101T nNUVv-NI1 SETEBMMaIIN antibodies A-1 5101T 36 nUV-N2 MITROSOMTOMAOBUKOa antibodies A-1 5101T 37 nNUv-NZ ASTI EAU antibodies A- 1(51017T 38 nNUVv-I1 VABOVMU5TAV antibodies A- 1(39nVIv2) WILL TAKE 5 antibodies A-1 5101T

NUVv-I WITH OOUUTTATT antibodies A-1 5101T 41 Variable EMOY MEBYASIS AND MOROSBI VI. ZSAAZBOAETET BMOINMUMUVOA region ROaKai EMUUSI IBRAVIOTOM AMZUKOAVETI BAOTO5KMTAU heavy GOMM5I VAEO TAUUUSAA!MO MOMAgEMAzaMm rimaOstI MT 55 chain antibodies B-3

42 Variable IOMTO5RBB5 AND BABMOaOVMT ITSVABOYUM5 TAMAMUMOOKR region of the lung OKARKI IM5 ABERY U5OaMRO VEZOaBOaBaIto ETI TIZ5I OR chain EORBATUUSOO 5ETARRTERSO STKMEIK antibody B-3 43 Framework RIOMTO5RBB I ZAZUSOVMT ITS region of the 1st lung

EC) antibodies A,

A-1, A-2, A-1 5101), B-3 44 I 0C-eE2 antibodies | MUMOOKR SKARKI M

A, A-1, A-2, A-1 5101), B-3

And 0C-eKZ of antibodies | СМР5 NEZOaBavzato TI TIZBI OR EOBATUUS

A, A-1, A-2, A-1 5101), B-3 46 and C-EB4 antibodies | EFO STKMEIK

А, А-1, А-2, А-1 5101), В-3 47 Framework EMO MEZO AND MOROSBI VI SAD region 1 heavy chain (НСо-

EC) antibodies A,

A-1, A-2, A-1 5101), B-3 48 NO-EE2 antibodies MMVOA YEARS! EMUM

A, A-1, A-2, A-1 5101), B-3 49 HO-EEZ antibodies VETI BAOTOKMTAM AND OMM5I VAEO TAMUMSAV

A, A-1, A-2, A-1 5101), B-3

HO-ERV4 antibodies SOS and MTU55

А, А-1, А-2, А-1 5101), В-3 51 IdDa1-severe EMOY MEBOSIE AND MORISBY VI 5SAABAyetTev MUaINMUMUNOA chain ROaKageMMOaMm ITROSamMtTOM AOBUKOVETI BAOTOKMTAU antibodies A-1 GOMM5I VAEO TAMUMSAVAS TI EAMM/SOST ITK M151AVTM ) SRBOMERI ARB5 5K5T5aaITAA OSI MKOMER ERUTUBUM5O

AI T5OMNTER AMI 05501 5 I 55BMMTURBB 5 aTOTMISM

MMNKROBMTKM OKKMERKBSO KTNTSRRORA RE G SSROME

HERRKRKOTI MIZATREMTO MMMOMZNEOR EMKEMM MUR S

MEMNMAKTKR VEEOUMZTMA MMBMI TM NO OM/I MOKEMKS

KU5MKAI RAR IEKTIZKAKOa ORAEROMMTI. RROVEEMTKM

OM5I TSI UKa EMROOIIIIAMEM EBMOOREMMMU KTTRRMI 050

SOR MK MOKSAMOSSOM MEZZSZ5UMNEA AND NMNUTOKOBI. 5І Рак 52 ІдДа1-важкий ЕМОЇ МЕБОСІЄ І МОРИСБІ ВІ 5СААБОЄТЕ5 ММОІНМУУВОА ланцюг РОаКагЕММОаМм ІТРОСамМтТОМ АОБУКОВЕТІ БАОТОКМТАУ антитіла А- ГОММ5І ВАЕО ТАМУМСАВАС ТІ ЕАММ/СОСТ І МТМ55АВТК 1(5101Т) з СРБОМЕРІ АРБ5 5К5Т5ааИТАА ОСІ МКОМЕР ЕРУТУБУМ5О мутацією АЇ Т5ОМНТЕР АМІ 05501 5 І 55БММТУРББ 5 aTOTMISM

Mm297a MMNKROJMTKM OKKMERKBSO KTNTSRRORA RE sa RBME

HERRKRKOTI MIZATREMTO MMMOM5NEOR EMKEMM MUR S

MEMNMAKTKR VEEOMOaAZTMUA MM5MI TM NO OM/LI MOKEMKS

KU5MKAI RAR IEKTIZKAKOa ORAEROMMTI. RROVEEMTKM

OM5I TSI UKa EMROOIIIIAMEM EBMOOREMMMU KTTRRMI 050

SOR MK MOKSAMOSSOM MEZZSZ5UMNEA AND NMNUTOKOBI. 5I Cancer

53 Light Chain | OIUMTO5ROB AND BABMOARAMT ITSVABOVM5 TAMAMUUOSOKR antibodies A-1 SCARKY IM5 ABRI 5IaMRO NEZOBOaBYto ET TI OR (5101); easy | EVEATUMSOO MUTTATTRaO aTKMUeIKATM AARBMRIERR CHINA ZOEOI 5BMUMSI AND MMEM REEAKMOMUKM OMA! OBYaM5O antibodies A-1 EBMTEOBKO 5TU5I 55T1I TT | ZKAOMEKNK MUASEUMTNOS

I 55RUTKOEM NSES 54 Variable EMOY MEBOSIE I MORISBI VI 5SAABOETE5 MMOINMUUVOA region ROK EMMOaM ITROSSUTOM AOBUKOVETI BAOTO5KMTAU heavy GOMM5I VAEO TAMUUUSANAS ХІ EAMM/SOST I TU chain X is any amino acid except 5. antibodies A-1 oh

NUV-NZ ASHI EAU antibodies A-1 X is any amino acid except 5. oh 56 IdDa1-heavy EMOY MEBOSIE AND MORISBI VI 5SAABOETE5 MMOINMUUVOA chain ROK EMMOaM ITROSSUTOM AOBUKOVETI BAOTO5KMTAU antibodies A-1 GOMM5I VAEO TAMUUUSANAS ХІ EAMM/SOST I U55AZTK (5tO1X) SRBOMERI ARB5 5K5T5aaITAA AXIS MKOMER ERUTUBUM5O

AI T5OMNTER AMI 05501 5 I 55BMMTURBB 5 aTOTMISM

MMNKROMTKM OKKMERKOOSO KTNTSRROSRA RE SORBOME

HERRKRKOTI MIZATREMTO MMMOM5NEOR EMKEMM MUR S

MEMNMAKTKR VEEOUMZTMA MMBMI TM NO OM/I MOKEMKS

KU5MKAI RAR IEKTIZKAKOa ORAEROMMTI. RROVEEMTKM

OM5I TSI UKa EMROOIIIIAMEM EBMOOREMMMU KTTRRMI 050

SER MK MOK5AMOSOaM MESS5UMNEA I NMNUTOKOI 5I 5ROaK

X is any amino acid except 5. 57 IdDa1-heavy EMOY MEBOSIER AND MORISBI VI 5SAABOETE5 MMOINMUUVOOA chain ROKY EMMOaM ITROaSUTOM AOBUKOVETI BAOTO5KMTAU antibodies A-1 GOMM5I VAEO TAMUUUSANAS Х EAMM/ POST I MT U55AZTK (5101Х) with ERUTUBUM5O mutation AI T5OMNTER AMI 05501 5 I 55BMMTURBB 5 aTOTMISM

Mm297a MMNKROMTKM OKKMERKOOSO KTNTSRROSRA RE SORBOME

HERRKRKOTI MIZATREMTO MUMMOM5NEOR EMKEMMU MU OSS

MEMNMAKTKR VEEOMavtUA UMBMI TMI NO SUMI MEOKEMKOS

KU5MKAI RAR IEKTIZKAKOa ORAEROMMTI. RROVEEMTKM

OM5I TSI UKa EMROOIIIIAMEM EBMOOREMMMU KTTRRMI 050

SER MK MOK5AMOSOaM MESS5UMNEA I NMNUTOKOI 5I 5ROaK

X is any amino acid except 5. 58 Variable EMOY MEBOSIE AND MORISBI VI 5SAABOETE5 MMOINMUUVOA region ROK EMMOaM ITROSSUTOM AOBUKOVETI BAOTO5KMTAU heavy GOMM5I VAEO TAUUUSAVAS HM GAMU sOST I MTU55 chain X is any amino acid except 5.9 A NU antibody - НЗ АСХМЕАУ antibodiesА X is any amino acid, except 5. (5101Х); NUV-

НЗ antibodies A- 2(-5101x 62 Variable EMOY MEBOSIER AND MORISBI VI 5SAABOETE5 MMOINMUUVOA region ROaKageEMmmmam tamMMasUvoM AaOBUKOAVETI 5BAOT5KMTAU heavy GOMM5I VAEO TAUUUSAVAS HM GAMU sOST I MTU55 chain X is any amino acid except A-25.

63 IdDa1-severe EMOI MEBOSIE AND MORISBI VI 5SAABOETE5 MMOINMUUVOA chain ROaKagEMMOaMm ITROSamMtTOM AOBUKOVETI BAOTOKMTAU antibodies A-13 | GOMM5I VAEO TAMUUSAVAS 5I EAMMU/SOST I MTU55AZTK mutation SRBOMERIARB5 5KOT5IaSTAA I SI MKOMER ERUTUBMU Ma

Mm297a AI T5aMNTER AMI O5501 5 I 55MMTMRBB B aTOTMISM

MMNKROBMTKM OKKMERKBSO KTNTSRRORA RE G SSROME

HERRKRKOTI MIZATREMTO MMMOM5NEOR EMKEMM MUR S

MEMNMAKTKR VEEOMOaAZTMUA MM5MI TM NO OM/LI MOKEMKS

KU5MKAI RAR IEKTIZKAKOa ORAEROMMTI. RROVEEMTKM

OM5I TSI UKa EMROOIIIIAMEM EBMOOREMMMU KTTRRMI 050

SIR MK T MOKBAMOSSM MESSOMUMNEA AND NMNUTOKOI. 5I ZRK 64 nNUv-NZ ASTMUEAU antibodies A (51017); NUV-

НZ antibodies A-2 5101T 65 Variable EMOY MEBOSIE AND MORISBI VI 5SAABOETE5 MMOINMUUVOA area ROaKagEMMOaMm ITROSamMtTOM AOBUKOVETI BAOTOKMTAU heavy GOMM5I VAEO TAUUUSAVAS TM GAM sot I MTM55 chains of antibodies

A(5101T

Варіабельна ЕМОЇ МЕБОСІЄ І МОРИСБІ ВІ 5СААБОЄТЕ5 ММОІНМУУВОА область РОаКагЕМУМУсаМм 1теамасУуомМ АОБУКОаВЕТІ БАОТО5КМТАУ важкого ГОММ5І ВАЕО ТАУУУСАВАС ТМ ГАМ сот І МТМ55 ланцюга антитіла А-2 5101Т 67 ІдДа1-важкий ЕМОЇ МЕБОСІЄ І МОРИСБІ ВІ 5СААБОЄТЕ5 ММОІНМУУВОА ланцюг РОаКагЕММОаМм ІТРОСамМтТОМ АОБУКОВЕТІ БАОТОКМТАУ антитіла А ГОММ5І ВАЕО ТАУУМСАВАС ХМ GAM SOST I MTU55AZTK (5101X) with SRBOMERIARB5 5KOT5IaSTAA I SI MKOMER ERUTUBMU Ma mutation AI T5aMNTER AMI O55021 5 I 55MMTMRBB B aTOTMISM

Mm297a MMNKROBMTKM OKKMERKBSO KTNTSRRORA RE G SSROME

HERRKRKOTI MIZATREMTO MMMOM5NEOR EMKEMM MUR S

MEMNMAKTKR VEEOMOaAZTMUA MM5MI TM NO OM/LI MOKEMKS

KU5MKAI RAR IEKTIZKAKOa ORAEROMMTI. RROVEEMTKM

OM5I TSI UKa EMROOIIIIAMEM EBMOOREMMMU KTTRRMI 050

SBERM5KIT MOKBAMOSSIM MESSOMUMNEA AND NMNUTOKOI. 5 AND 5 YEARS

X is any amino acid except 5.

ІдДа1-важкий ЕМОЇ МЕБОСІЄ І МОРИСБІ ВІ 5СААБОЄТЕ5 ММОІНМУУВОА ланцюг РОаКагЕМУМУсаМм 1теамасУуомМ АОБУКОаВЕТІ БАОТО5КМТАУ антитіла А-2 ГОММ5І ВАЕО ТАУУМСАВАС ХМ ГАМ СОСТ І МТУ55АЗТК (5101Х) з СРБОМЕРІ АРБ5 БКОТЗИааТАА ГГ аСІ МКОМЕР ЕРУТУБМУ Ма мутацією АЇ Т5аМНТЕР АМІ О55021 5 І 55ММТМРББ Б аТОТМІСМ

Mm297a MMNKROBMTKM OKKMERKBSO KTNTSRRORA RE G SSROME

HERRKRKOTI MIZATREMTO MMMOM5NEOR EMKEMM MUR S

MEMNMAKTKR VEEOMOaAZTMUA MM5MI TM NO OM/LI MOKEMKS

KU5MKAI RAR IEKTIZKAKOa ORAEROMMTI. RROVEEMTKM

OM5I TSI UKa EMROOIIIIAMEM EBMOOREMMMU KTTRRMI 050

SBERM5KIT MOKBAMOSSIM MESSOMUMNEA I NMNUTOKOI 5I 5YEAR

X is any amino acid except 5.

ІдДа1-важкий ЕМОЇ МЕБОСІЄ І МОРИСБІ ВІ 5СААБОЄТЕ5 ММОІНМУУВОА ланцюг РОаКаїгЕММСОМм ІТРОСамМтТОМ АОБУКОаВЕТІ БАОТЗКМТАУ антитіла А ГОММ5І ВАЕО ТАУУМСАНАС ТМ ГАМ СОС І МТМ55АЗТК (5101) з СРБОМЕРІАРБ5 5КОТ5ИаСТАА І СІ МКОМЕР ЕРУТУБМУ Ма мутацією АЇ Т5аМНТЕР АМІ О55021 5 І 55ММТМРББ Б аТОТМІСМ

Mm297a MMNKROBMTKM OKKMERKBSO KTNTSRRORA RE G SSROME

HERRKRKOTI MIZATREMTO MMMOMZNEOR EMKEMM MU S

MEMNMAKTKR VEEOMavtUA UMBMI TM NO SUMI MEOKEMKOS

KUZMKAI RAR IEKTIZKAKOa ORVEROMUMUTI. RROVEEMTKM

OM5I TS UKOa EMRBOIAMEM EBMSOREMMU KTTRRMI 050

SOR MK MOKSAMOSSOM MEZZSZ5UMNEA AND NMNUTOKOBI. 5І Рак 70 Ідс1-важкий ЕМОЇ МЕБОСІС І МОРИСБІ ВІ 5СААБОаЕТЕВ МУСІНМУУВОА ланцюг РОаКагєЕМмМмам тамМмасУвомМ АаОБУКОаВЕТІ 5БАОТ5КМТАУ антитіла А-2 ГОММ5І ВАЕО ТАМУУСАНАСЄ ТМ ЕАУМ СОС І МТМ55АБТК (51011) з СРБОМЕРІ АРБ5 5К5Т5ааИТАА ОСІ МКОМЕР ЕРУТУБУМ5О мутацією АЇ Т5ОМНТЕР АМІ 05501 5 І 55БММТУРББ 5 аТОТМІСМ

M2970 MMNKROMTKM OKKMERKOOSO KTNTSRROSRA RE SORBOME

HERRKRKOTI MIZATREMTO MMMOM5NEOR EMKEMU UU OSS

MEMNMAKTKR VEEOMavtUA UMBMI TMI NO SUMI MEOKEMKOS

KUZMKAI RAR IEKTIZKAKOa ORVEROMUMUTI. RROVEEMTKM

OM5I TS UKOa EMRBOIAMEM EBMSOREMMU KTTRRMI 050

SOR MK MOKSAMOSSOM MEZZSZ5UMNEA AND NMNUTOKOBI. 5I Cancer

Mmp(X1uhgashya(x3ruAovUKa nUV-H2 KhIieRabos; xX2 is either M; X3Z is T or 5 nNUVv-NZ XtIe5 or tT; X2 is M/ or I.

NUV-NZ (101X) | X1 is any amino acid except 5; X2 is UM or I.

NUV-NZ (101T) )X1 is M or I.

NUV-Y Z Khie5Zabom; Х2 еРаброд;хзЗ ев or t 75 Light chain | OIUMTO5ROB AND BABMOARAMT ITSVABOVM5 TAMAMUUOSOKR antibodies A SCARKY IM5 ABRI 5IaMRO NEZOBOaBYto ET TI OR

EORBATUUSOO 5BUTTRRTROO STKMEBIKATM AARBMURIERR

ZREOY KBatTA BMUSI HER MMEM REVEAKMOMKM OMA! O5amMmBo

EBMTEOOBKO 5TU5I 55T1I T | ZKAOMEKNK MMASEUMTNOS

AND 55RUTKOEM NSES 76 Light chain | OIUMTO5ROB AND BABMOARAMT ITSVABOVM5 TAMAMUUOSOKR antibodies A-2 SCARKY IM5 ABRI 5IaMRO NEZOBOaBYto ET TI OR

EORBATUUSOO 5BUTTRRTROO STKMEBIKATM AARBMURIERR

ZREOY KZATA BMUSI HER MMEM RVEAKMOM/KM OMA O5aM5O

EBMTEOOBKO 5TU5I 55T1I T | ZKAOMEKNK MMASEUMTNOS

I 55RUTKOEM NSES 78 Alternative- |MMaIIIN ny NME-NI1 antibodies A, A-1,

A-1 (51017),

A-2 79 Ids1-severe EMOY MEBOSIE AND MORISBI VI 5SAABOETE5 MMOINMUUVOA chain ROKY EMMOaM ITROSOaMTOM AOBUKOVETI BAOTO5KMTAU antibodies A HOMM5I VAEO TAMUUSANASE TM EAUM SOS I MTM55ABTK (51011) SRBOMERI ARB5 5OSERKUBTKOMER M5aa5AO

AI T5OMNTER AMI 05501 5 I 55BMMTURBB 5 aTOTMISM

MMNKROMTKM OKKMERKOOSO KTNTSRROSRA RE SORBOME

HERRKRKOTI MIZATREMTO MUMOM5NEOR EMKEMMU US

MEMNMAKTKR VEEOUMOTUV MUBMI TM NO OM MOKEUKS

KUZMKAI RAR IEKTIZKAKOa ORVEROMUMUTI. RROVEEMTKM

OM5I TS UKOa EMRBOIAMEM EBMSOREMMU KTTRRMI 050

SOR MK MOKSAMOSSOM MEZZSZ5UMNEA AND NMNUTOKOBI. 5I Cancer

IdDa1-severe EMOI MESSOSIO AND MOROSBI VI ZSAABIETEV MUSINMUMAOA chain ROKaGgEMMOamM IToeMmasUuBOom ArBUKaIavVETtI BAOTZKMTAU antibodies A-2 GOMM5I VAEO TAMUUSAVAS TM/RAUMY,OST I MTUBBZABTK (51011) SRBZMERKOMBERGARBZ 5K HZBI OSRBY

A T5OMNTER AMI O5BYI 5 BZMMTMRBZB BI ETOTMISM

MMNKRZMTKM OKKMERKZSO KTNTORRORA REGI saRBME

HERRKRKOTI MIZATREMTO MUMOMZ5NEOR EMKEMU US

MEMNMAKTKR REEOMMZTUA MMBMI TM NO SUMI MEKEMKS

KUZMKAGRAR IEKTIZKAKO ORVEROMUTI. RROVEEMTKM

OMBI TS Ka EMRZOIAMEM/ EZMOOREMMM KTTRRMI OBO

OBERIG MKIT MOKBAUMOO, M MEZZZUMNEA AND NMNUTOKBI. I Zrak 81 IdDa1-severe EMOI MESSOSIO AND FROSTS AND ZSAABIETEZ MMYainNMUMVOA ROKOGEMMSOM ITROSSUTOM chain AOBUKOAVETI BAYUTZKMTAU antibodies A-1 GOMM5I VAGOI TAMUMSAVAS 5I EAMMUSOST AND MTZAZTK

SRBZMERGARBZ 5KZTBYAAATAA GG OSI MKOMER ERUTUBMMZO

A T5OMNTER AMI O5BYI 5 BZMMTMRBZB BI ETOTMISM

MMNKRZMTKM OKKMERKZSO KTNTORRORA REGI saRBME

HERRKRKOTI MIZATREMTO MUMUMOUM5NEOR EMKEMUUUYUS

MEMNMAKTKR REEOMMZTUA MMBMI TM NO SUMI MEKEMKS

KUZMKAGRAR IEKTIZKAKO ORVEROMUTI. RROVEEMTKM

OMBI TS Ka EMRZOIAMEM/ EZMOOREMMM KTTRRMI OBO

OBERIG MKIT MOKBAUMOO, M MEZZZUMNEA AND NMNUTOKBI. And Zrak

PEBENIK SEQUENCES

"MOB obENEMTESN, IN. "Eat, SLEEP, what Udao

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Zh "Ah and "Ya VE "Ii" villa and "Zh" fat sequence "ad" "823" synthetic sequence: variable region of the light chain of antibodies d-2 "still b "vro Iiv ship Mei tvb osiv begorgo zegobeg o gvu Bek ATa run ma! bih 1 5 10 15 ar Aha Uvi tagoiI1ie tvgobuz Ag did zeg soi der oudi bag tar aa 20 25 za

Uai ARV tgvotuk ip bib Uh vto bi uz did Rg yuuz ip ieen IЇe

35 BYU Ya tug dvg ATa bek Re ivy tugo bvgob1iu Uvi Bko zag oaga BBe beg siyu zi ZE bo

Zee siu ek o biu ta OA RBe tyg oiets tvgb ot) Beg 5ek yivu Biy go ta 72 what yiizim AB Rlyu aa tv o tug tugo Se biv biv o jekK tag Tv o tVg RO vgO 8 what 5

Ts ovna evku biv biu tpgoizhz ma? network 5 "OO" gu "9 Z "8Zye vil "233" artificial sequence "WTO "EE3" synthetic sequence: NUV-NI antibodies A-2 "VO" g o5iu vva tik orav bat o ashchi tugo siu tI1v nih and with "En" and "231" 15 "Ezha" vBidok "her" artificial sequence "B" "B28A" synthetic sequence: nNuk-ne antibodies 4-2 "VM" Cat tta ty tak obiU Ap ovi Bi tuk zer az; 5 5 15 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 7 ten re Aid tug i 5 eV: For "Asia" With "a" vozzhZ "2i3" artificial sequence of stv "vi" synthetic sequence: NUK-IZ antibodies 8-2

"Aya aha Ata Zvgobiv ABr oba! bZeg tngo div Uvi Aidy o ip predatory" ZI "eyelash" 7 "ey BZlOOK "eiyiz artificial sequence kggOh "eyy" synthetic sequence of nUn-Ri 2 antibodies A-2 "Mykh li chvg div bek vreiv tu shcheg y 5 "ee "her" Z "Vil" viLOK "213" artificial sequence "ee "VAH synthetic sequence: NUK- Z antibody A-2 "Vo" 32 i-iv bi hek Tuk tTBt o tvg orga Vgo tTVg i I 5 "Fa" 43 "hygies" Хх гиг" BilOOK Y Y "2I13" artificial specificity "220" y y Y Y "ra" synthetic sequence: variable region of heavy deer antibody

A-IBIVit "WHAT Zh tsin zhar vip ien mni siv Zeg siyu shiu bi ivc omai bij ovgo BiZh oi1u 3 5 for 15 zagivy akd o iev o leb Suz Afd Aa zegobiu RBe TK o RVE chego oAshchi Tugb ha rya KI; -iu hKa niya tgrouvi Aga bij vid vko biu uhie be siy tkrokdi 35 40 45 si teroItIiv tk oRKgOo ar osiu viu tuye tng oder tuye Aid dyar o chet ha v 55 what iu« tu Aga RNe tk otiv heg Aiv AzrotnNg bag oguh Aa tyK oATa tug to ha ka ivy shiy Met aZp Bek oieb Aga div bij a5r o tyg o ABa zhmai tuk tut sub 85 za Z "iz AgO AiV biu tBg iv RVE Aia tugo tgvosiu zip ЕTU tvgoivo ud!

NO 105 FROM tTag oUVi dec Bug 45 "eV" For "aiyh 107 "2Ityh vZLOK "213" artificial sequence "vah "223" synthetic sequence: variable region of the light chain of the antibody.

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TEG Oovav osi bij so1u tvg og uv UVK Bi IYishv vukh

MORE 105 "2305 35 "gii" "Rai BeloZh "gi3: shtuzna sequence "dach "2E3" synthetic sequence: NUVB-NIi antibodies A-iZSPITTI "meh 15 si vBe tak o vBe ego dep o tug shi lived NI5 i in her " A" Зб "her" 17 "еий" вилок "her" artificial cosequence "вед х "283" synthetic sequence NUV-NA aztvtida A-ZG IT "or" zv terotte te o Rgo Azroeiiu iu tug tVgoAxYu tuye Aia Az bag ouai gu ii Z zo 15

-iu "HER 37 ha Y "vii" video "233" shshtuzna sequence "eh Y y "223" synthetic sequence: NUBSH-NIA antibodies A-1G "pit "an zhi ziva BU tvg o gets Be ATa tuk y Z "B » ZK "VI ZI "Za" Bilak "813" artificial sequence "au" "823" synthetic sequence: NUK antibodies A-ZG8301tI "Ole Z aga viz hek bij avromai Zag otpt Az ud! Aides ii 5 her "her" Z "Iii 7 "212 VIDOOK "ei3" artificial sequence "22dh "RI832 synthetic sequence: NeKv-2 antvtila A-ZG LIT "NNh Z ego div 5eg re ivu tuk o chevg yi Z "Zah 4 "Vii" V "V" Biloch "Ii" artificial sequence "I Same "VEH" synthetic sequence: BUuk- 3 antibodies A-3 (5i01tI "ab" 40 siv bBip tuye tugo typgotVg action tb ote 1 5 "21 8 "gii » 123 "2Iiykh VILLOK "2Ii3" artificial sequence "veVh "vah synthetic sequence: variable region of the heavy chain of the antibody.

"kyu and eits chai bij gheets mai bin hek osiu Biu viu ren ouvi siy Bho siu 3 1 With her 15 zvegoivy Aga Betz zak obuz id Aiv o Zeb o shi Re tv o vBBe tvgoZeg tukg o Ka za

AvBrotie niv tgromai dga sii liz RgO bi rukh biv vets biv tKroma! 35 in yah -iu SOIU hie Zag o RgoOo did ahr bi der tagoABva o tug AЯa dep o zegotdi 50 55 that izh5 biu aga RA TBg oti bag Aida Azr o tagobeg uz Aza o tvg o Aiv tuye 3 7 75 EV ign sip met dey bek oivy aso Aia siy ah tVg div UVI here M uch y that Z

Aia aga aAzp o azo o tTuk yzv mai Aga RBe Uvi 5iu bek siu Mei AV otuk tyu ih o tgtrozih biv siu tpgogien ma? tab Uvi burning ag

From 120 "V" I "et" I "from" veloc "813" artificial sequence "eV" "va" synthetic sequence: naridbyelna blaset light lanishyuga antibodies 2-3 "hy avyurottie vip Mei tg biv chek rgo Beg Zak oivc beg action beg o udi vi i Z o 15

Azov oagad mai tv tiv tvke oSukh Aga aAia vo biv Azromaii 5egotvg div 20 25 5

Uvi Aid tga o tug vip vip uh hgo biu iu5 dia RHO iuB in i ats IV 35 aa 45 tug cheg Aid Zvg Re gen otug ego s1u Uudi go dek Aga Me Zegoshiu o 55 50 ak biu ek Zi tak ar o RMe tygogem tk oIzhIIv ek zak oivu shiy rga

EX; 5 vo si Aza vne Aid tyg ote tuk sub bij sip beg Re tvg o ATa vgo Rgo ih Zo 5 tt ovne shiu biv bi tVgoiuzh udi Sim tiv uh tyu 105

"VM" 43 "Vi1- 23 "Vil" BILAK "her" artificial sequence "Y" "223" synthetic affinity: the Caucasian region and the light chain ГРИ-РНИ) antibodies y, y, А-, АЗС, 8-3 "Oz" 43 der Iiv sii met tVkosii 5egoRgo yavgozaek ren hek div begouzi biu ii x 10 ih

AB оАКд чай ТЕГ жив тагосях кох "2" 44 "21іх 15 "вий" ВИЛОК "813" artificial sequence "ВВ" "В24" synthetic sequence: ES-BYA? antibodies A, Aa-3, y-2, A-ZKB5IOiTTI, B-3 "VO aa tro tugo ziv biv iuz ego si 5 div RGO uh iv ten Ii tuye i 5 i; 15 "28105 45 "31" 32 "her" WHITE . Y "IZ" artificial sequence keiO" k C z p s "vv3x synthetic sequence: C-Bva dntmtiy y, A-i1, a-2, A-1C 5 Ti, B-3 "I" 45 oZiu chai rt beg Ag o RNE Zet shi ek bi Bakrobiu TBE o Ahr RVE TNK i Zyiv 15 ivy tTvg oti Zag oBeg gay bij RKO 5iy Aho RBe led tVgotug tuk Su that "20" 46 "vi" Z "12" viVOoK "her" artificial sequence ke "KZ" synthetic sequence: С-РВЯ dntitiyp A, y-1, A-2, A-1(Г530ітТ, 8-3 "Oh Zv vpe piu Biy shi tagofuz ma! biy I) and in ii 5 10 "Uh 47 "IZ" 25 "2y2g PROTEIN and Y "lashes" artificial sequence

"VE house" sentential sequence: framework region 1 of the heavy chain "nNS-EVI) antitivz A, A-i, y-5,. 8-05 tTR, 8-3 "Ve 4u zin zav ziv ben ma) Bin bek siu biu biu ets o udi bip vgo Bi piu 3 a Z 35 ek ivc agd iiyev chego sSuv Aia A1iv Bag o a "riy: 48 "21iz A "Rid" PROTEIN "Rii" manual sequence "220 "?2Y" synthetic sequence: VS-BK2 antitia da, 8-1, a-yi, A-1G5i0it, v-1 "ayu av tktrozhai Ago viv Aid Rvgo siu uv еиу вм осив tgrouai еи1у и 5 за и "EV "im ZY "aiy" BINOK "gii" artificial sequence "ve" "reEVM" zhKinthetic sequence: HO-RKZ3 antetiv a, 4-ii, 8-3, A-M at ), k-3 "a" 49 aga vVe tngoIiv zZeg Aia Art tn Zegoiuz azp o tnkK o ATa tag oi vy biv ii 5 5 15

Met ha beye ivo Aga aa shi o yar o tvpg liv mai tuye tugo sSzhe ATa go 85 Zo "Em ZO "ii TR ch"vigU BIVOJ hAiZ"U artificial sequence "EE" "83" synthetic sequence: NS-BBYAA antibodies and, A-y, A-?, A-ZGeZ01tI, B-3 "ag 50 tgv Bi called osi tvgoiya tai tv mai Hekobes ii 5 10 "210" 51 "231" av "23" PROTEIN "IZ" artificial sequence "eV" "vva" svetetic sequence: tdbi- heavy chain of antibodies 8-15 "aOiyue Zi sim chai bii yiv Uaii bii begobiu biu viu fev Uvi shii Rga siu shi i 5 ii ii5

Zeg ivts dgd oiivy zagos su Aia A1id Zekobiu Be tb o RBe o beg Ap Tug 2 28 za zi zhiv niv tgtpomai dk bib led vgo boiu uz z gen siv tgroUdi 35 0 45 b5iu tgrotiv tk oBgo ahrobiu shizhZ tTug tAg o ABr o tukg Aaia der 5eg ouvi 5 86 it Btu Akad o vMe tygoIie heg Aza art tk Begoguh dep tv oAid tug that 7o 8 that yivy Biv mee d5po5zeg o yeets dgo ii Bii OR g oATa wai tuye tug Sub 5 ro 5 div Ag AtTa siu tak oiets vBe A1a here tgrobBiu oTpy Bi tVe oigc mai zo 05 zlo

TVg oUai Zecodeg did bag tag movement yaiu Rga chego udi RBa o wgo ziv Aia 115 i2a 125 rgz Zag vak obu chego otpg obeg si biu TBgoAiv Av grec siu suv i vy

И30 и1х5 3 chai uh yshkr tugo vBe wkgo bin wgo mai togoUvi ego tov o Adyap o 5eg o biu zach yi5a div iecch tk zak obiu mvi nii tpgoRBV vgOo ATA UVI in Biy heg o zeg yi65 Z 1-5 siug ge tuye jakoien obeg ego udi Udi tTichk o maii Rgo zvgoZeg zeg oyi vu ih i85 90 siu tag bij tb otuk tiv Sez Ayap o mai ABY Niv ruch Rko bek ABY OT 195 zob Oh iu5 ha! AB vuh uh Uudi ish rgo iubB Zeg sub AB U TVKONiv TV z16 215 220 yuuz Rgo Rgo buh Rgo Aa Rgo 5iy ivy tez si fu Rgo hek ma! RBe ah «Zo 235 245 ivy vne RgOo ego iu5 Rko rub Ar tTpg oivy Met tiv Zvgbodka tpgorRgOo yo a KZ

Ziy mai tv osSuv di Uvi Ua! aho Udar hek niya 5 OR ego biv Uvi a zva tto it5 Rpe Ap tgrotug chai der vih Uaf zii mai ih Aza ATa ruh tk at oh tk

TYA5 EI Vo iush vKgo Aga Bin ish bij tugo dey hakotvg o tuk zga ma) chai bek oUdi 220 25 for ivy tpgoUai ivy nih vip aa tkrivn dl shpim ate sit tugo fu Sub 305 zp zZi5 zgo zjue uv! Zak A5p oi uz Aida iva RgOo div rgo o Ii8 viv i f5 otKK tiv Be 345 330 335 iz Aiv yuuh shi biv ho Agd o bish vgo biv ud) tuye tvroivu vgo vgo

Bez zaz i50 eg aha ich Zi met tngoiv5 Aby bip Uaii dec ofets so osSuye ivey ma! 355 zo 355 iuv biu RBe tug Bho bZeg avr o tie Aza wai vii tgr osiv Zag oavp su zt zaz za bZip Rgo biv Avpodyap tugo imoe te otikK o rgo Rgo Uai iets o dyar bag OR 285 390 za5 to bZiu zvg RE RE yiv tugo bag oguz vp otVgokhaii z5V gub 5EG AgOo ttr 05 10 315 vip vip ziu Avp Ua RM beg o was zako udi mei nii sich did yiv: NIi5 zva 25 330 dav Ni tus TK Obii gu5 Bag oieets zhegoivu beb vgo Bim ih 435 zda 445 " Mr. I? "21i" 4465 hai2" PROTEIN I Y "IZ" artificial sequence "evoh Y "gaZ3U synthetic sequence: tubzi-heavyMm chain of yantiktype A-1(5NNTI with mutation Moy "Ne ZY bZits in zZip fen ozhai 5zin bag sSiu 5iu pi gay chai I know the fight

Z z 16 15 5egogem Aga iv Zv oSuz ALA Aa bek obtTu vna tak rve zeg Ap otuye o 25 i5 sik hiv niya tro oMai Aga ip dia vko Bi gu shi rev obii tgrocha!

U Ya siu ter oITe tproBgo Avrobiu biu tuye taig o Avrotuk AZa Ar obeg chai 5О 53 5 izh5 Biu Aga Ra twkKoii8 ego AЙХ der tyag bek otu A5a oTvpgOAiV tuk 85 7a t5 that ivy bip Meii AB zekgoivets dk Aid siy ar tag ATa hai tuye tug KSuz 55 shcha 5 div aga ATa siyu mountain vve did here tgrobiu biv bi tvKoivy mai 155 a tvgozmai bBeg hek ATa be tTBgoiue sSiu rgo bek vu rpe Rgo ivey liz 15 25 125

Rg hagobek fu des tagobek s1iu siu tvgb oaiv Aid gvets o siu was and you i54 i35 ate chai uh dya tuye vverez bich who mai tvgoUai zego tro o Ayavy bek osiyuu 145 RO 155 150 aia ivy tk obek sim zayi Niya Teg ope o rRgo viv Uzi gen osiv begobvo 15 15 ih siu fen tug hvgoien bag o begoUudi Uaf tk oUvi Rgo 5eg o bek heg oi en y85o i855 Iza siu tak obit tk tugo yii Su Ap Uvi dyak niya gu RO Zek give tn 155 2ОЮ 2a5 iuz chai AvrogUu5 uz ud! Shiyu Rgo iu« Zag buh Aurorauv tag No such 1 TI gay pu Wga vgo buh Bkgo deia Rgo sim gen gay shik biu Bra ego huaiZ vne gE5 250 255 ai ienp vNa wgo rga gu vo i zha AZO Tygoieets met tiv yav Aga tk ovga zaz 256 85 zh ah sha chiy mai tvg o sSuz Uudi mni mai Az in Begonia b1Ш Ah RKO si hdi "B zva ky iuz vne Avp tko otu ma? dyar bi uv zi) Uvi nih di ATa gu TNK au go 2855 uz rTv Ago shi biv siy 3 vZiu ego tik tuye tuto chai Ua! New Year's Eve

For B for iets tvgoUudi Benz ni zip ar oito oiven azy sie ie sie sin tugo ru Suh

ZB zyu 315 120 iuya uv bek a5p gu Aiya ien wgo div Rgo tiv biv vuh tvgoIiv Chet 125 z35 255 325 335 3:5 yuuz liv uv vih siy vgo Aga sim rt sipoUudi tTuk tv oivu rRgo vga 380 45 830 vk aga o osiv Met tt oiuz dyap osiv Uudi bek oivts so oSzhz you udi

370

ZE: zza 335 Zo biu ego RCha rBv iivu tTug heg o guz gen otvgouai Aevit 5egoAga tgr cha5 zla 4315 vip ship with Avp o Uai RyEe begoSuv bek in mei niia si Av i ev NI aga 425 430 dep oniv tuk tVag Osii uz bag oivc bZekoy vu 5ekovgo siu ikh 335 a40 485 "I" Za "EL 14 "keii" vidok . And "vis" artificial sequence "Oh "83 c Synthetic sequence: light chain of antibody A-31G 5301); light lypantsyuk of A-type antibodies "ex 53".

Azy otie schiv Met tk osiy et wgo dec bag oivu 5ek Aia ego tdi si1u iiy z 10 15

Azy aga chai tp o ITe tygoSuya aga aZia beg din Ar oma) Begotvg Aia o She BI chai Ata ter otuk biv siy tooth Rgoa siu yuuz Aa go fu im oyi vi tiv 15 AB a tug bek Aid BEK RVV gi tugo Zeg osi uv rgoa jek dgd vne zheg o biu

Zv vo zeko»iu bBeg z TVK der yaye tTVgoiem ts tiv Bek hek oivc siv vga b: 7o TB that bid azr Re Aa tv tugo tugo sSuv bip stand tugo tuje tb otng Ai o tNe zha 5 z5

TVgoRNe biv sip family of tvh oi Uai bin ITae uv Aga otvg ma! Aid A1a 00 305 that vga ek uai Rye Ii BMe RKO RGO zak oABr oZiYu siv gvc o iu5 bak obiu 115 125 125 tvgoaia es omai Mai Su5 iv iets dya dev rye tuye vga Ak shi: dyd 130 135 her it ma! siy tgriuv udi ABr dp ATa hecs osiv Beg biu Ap Bag osiv i4x Io 155 iv sin zag o mai tVg obi bij abBr hek oiu5 Abrozag tvg tuye zako ogetsn Bag ii55 1u6 175 ek otng og) p ivc o 5ekoiuv A1d OR tugo bBic iuz No and both that 150 355 and action sSu5 beat ma! tVgonih vip biu iv bek obek ego udi TVHoiuz Zag

IZ ME 25 re ap odha viie Bin sSukh "Io y Y y "yuyu va "21" SCHE "yy" Belok y . кеЯЗ3х artificial sequence ке І , p. . "28Х synthetic sequence: variable region of the antibody heavy chain

A-SNIH "vah "lashes" other signs "avg (MN. NN y y Y "R23Uh Hva maje yavlyutm any dMino acid, Kyi schesg "dk Za b5its Uvi bBip o giek wai bin Zvgobiu ziu stu be) o Uai bip ko z s1zhh iy Z 19 15 5egiem Aga yeets B5eg sSukh AЯa did hek o biu wats ve 5eg dop tuye a 25 Zo siu htiv ni tgroUVi aka shiy did wgo zi U bizh you bib tgromai

AV Ya5 siu tgrohiv tk oRgoe der oviu biu tugo tyag oAza tuye iz Ar o Beye mai 0 5 Ba uz si Aga RVE tVgoiiv 5eg AZiV Aho tag hek oiuz ap o tlg Aid tug 3 te 75 that iets biv Meg Azpozhegogen Aga AV bin OR tk o ATa mvi tugo tuk Suk i5 cho ah "13 ako div vih Havoien vVe did tugo tro shi ziv biu tgoiven o udi 190 105 Her

Tygomai ego ver her "ayu for "And I, "eI2" BIVOK

"vIi3U artificial sequence "ED" "TZ" synthetic sequence: NUVB-NI antibodies A-Z (ZIOTHI "EE "21" other features "vvi 33..3 "RIZ" XxXva can represent any ayutnoic acid, Kiev ag s kha "ia stu hav fen vne diya tuye i 5 "20" ЗB "231" "AB "212" vIiLOK "lashes" artificial sequence keEOh kara" synthetic sequence: tIdb5i heavy chain antibodies 8-15 ih "ED" "riyu other signs "hara KMN)..SKN and I and "KTZ" Hva can be any amino acid, except for "ak U bin Uai vip ben ma? Bi Zeg siu yeiu stu vo Uai bip rgo vih siu i 5 15 i: ek iv zagov ven det sSuz Ai AiId zak osiu vNe so vav zag dy here

Kz: 25 va siu tt nih tgroudi Agorziip aia RGOo zZiu Bu SIU raz bin tgroudi eV Ya

F1u tgroIiv tk oRgo Azrodiu biu tut tagoaAvrotug A1iv azroheg mai 0 V Ba iu5 Tu Agd o RVe tVg IT bZeg A1V Aho tTvg hg fu ab tvVg AT tug

Bh ta 75 8O ietsp bip met dyai zag oivu Aga Aiv Bin or tik action to me tugo tugo sSukh 85 that ZE "ia aku div viu hHaa ivu Re A1iv tUuk tgroshiu biv s1u tvhogen uv zob 1535 io

Tygomai bek hek AIish beg tvgoiu5 eiu wgo beg uv Rae RgOo yvy Aia iiiiiih 125 15

Bho Beg beg uz ego tnpt hegoBiu bi tpg o ATa Aid hav biu suz ivn 139 135 148

Uai iuvz Azp tuk RVe Rgo action Rgo Uvi tygomdi es ter oda ego eiu 145 z58 155 i5a aiv ivets tygobZag si» Uudi Ni tik or rve RKO Aid mi yivev obip Zeg o Beg 155 i7o 355

Ziu yeets tug beg iets bZeg beg Ma! wai TVgohUai Rgo bZeb hek Zag oi gts io 185 195

Bi tagozip tab tuye Ii Suz dp Uzi az ONIZ rub Rgo Zzegodiai TVpg iz: po 205 iv iv mai ABYuv oiuv i di viyu Rg ijya ZakoSukh AV fu tVgoOnia tak 210 215 ki su vgo RKO Su Rgo Aia vgo Bii ivtsoivy bBiu si Rgo Zegoma1i rve ha 230 235 250

From the heat of tygoSuz Uzi di Udi ABrowdi ego niv bich av ovgo Bin Udi go 265 ki it RNe dp otgv otuk uai Ar osiu ma! Oty Uai niya 45 Aid gu Tpg tt5 "y B yuuz rgo agd biz siy bij tugo ABp Bek o tvg tuye AgYad Ua! ma! begohvi 299 295 300 ivy tagozhai yivu ni bij der tgroivy dzpobiu gu viv tegoruh Sub 305 M ZI zgo it mai beg d5poiuh Aia io rgo led Vgo hIIv SRits o iub5 tVgotie zag 325 3 335 юu5 Aid iu biu sid ro akviy vgo white TV oi ev vka Rgo zay 345 350 zeg dgo vii b0ish Mei tigoruz Aa viv Uvi hek o ren otv Suz gen uv 355 zvi ZBE iuUu5 bi VM tuye Bha Bagaze Iie div Uvi bib tgv siy zeg dya st 3709 37 zva ip tuo ZiSH AB Aa tugo Rukh TS OTP o wgo Rgo Uudi iv dr Zak Aho 385 zvo Zh SCHO s-iu Beg Rbe ne ren tug ego gu iv tygoUdi ABroiuh Zag AKYA tgo a5 410 315 step viv bi A5p o Uudi RBe ego buh 5eg o udi Met Ki Bib Hades and vts no 420 435 48a apnia tug tvg o sip yub ego ivy Bag obem zak Rgo siu gu

"from 30 345 "FA vu "21ikh 445 "ii" PROTEIN "21415 artificial sequence "vai" synthetic sequence: IPbSI- heavy antibodies A-Z(I5I0Я1Х With chain mutation MIZUE keyi" others however "Rai" KO. NM "223" xHav can be any value, except for 5eg kash Bi

Zina! biv ben ohai viv chet shiu B5iU Siu web wai siv wgo biu siu 1 5 10 1:

Zeg vy Aga iets ek Su ATa div bek siu Be tak orRBe zegoaha tut 20 23 zo 5iZ Ii niv tri Aga sip Aza Rgo StTZ uz bib ivy viyu tov o udi 35 Be 45 si tk oItie tk oRGO Avr obi biu tugo tag oAzrotug dia aA5rozeg ha 5 SCHO iv Biu Ag ve o tvKoi1e 5vegoAi ABrotag bek gu Ah o tVg Ota tuk a 75 VO iz bip Met dyapozekoivy Ago Aza sim der otig ATa mai tuk tuye sub

Eh cht for aAia aka Aa biu Had givno BBe div tug tgroviu biv sbiuUu tagogeb uv

SHI ZU 1

TVgH ud! age bek Aid Bek otBg oj biu rgoa age in Bergo gen Aa iih 128 125 vro bek zagruv bek TVg Zag obiu siu tygoAia Aid fev Siyu suzzien 135 i75 140 teas UZ AZr o tuK РVv vBgo Bi) Rgo Ua? TC ohdi es tgroahp ag o biu 135 i55 155 BO I potVgozZagodie mdi niz te vne vgo Aa mi iv; siy zvo dach div aries tvg ozek obi maiii niz tvBgovNe rgo Aa uv ev bij Zeg he) 155 170 195 biu ey Tuk beg ivu b5egohdet mai Ua! tTVgoUdi RGO bag hevgo bek i gu ii850 i55 iii bBiu tngoviv tab tuye tiv Sh Aa Udi Aazponiv uv Rgo BEg o dya TTG 1 taku 5 iiub5 Uvi AB gu uz mai pizza RgO gub ego Suh OR Ru tpg niv tve o 27i5 Ka

Sez Rgo Vgo Suz Bra ATa without bi ivmogeoz biu shim Bgo begouai ve 225 230 235 for iecz rRye vgo vgoOo and go iu5 to TNK oia) met ITe heg AK tvVg orga 245 250 53 siy mai TVgoSukh uai Udi Mai Azroud! why didn't AV do it? 25O 285 to iuch Re declared tgrotuk ma! Avroshiu chai Ti chai Ni Ap o AIv g uya TNK

I 28 5 iiu5 vgo Aga obBich Bish bij tug biu zvk o tvg tugo Agd o Udi Uvi ego ud! 2 2955 ZO ivts tvgoUai gen nih bip OR o tgroivts Aa siu yub bin tugo fu Su zi0 3I5 320 iz ma! shag dya iv viz iv rgo dia ego tt shi uh tpgOhYivV Zak 325 335 Za izzhz Aza gu Ziu Bi Rgo aga yei rgo sip Ua! tuye tygoivy Rgo rgo

Be Za ihOo veg aga Bits bits met ts oiu5 ap sii in Begobech tpkosSuv bez ma! 355 35 55 zu shiu Be tug Rgo Zvk Ar oIIV action Ua ziv tgrobits ego Ahp o 1u

ZU 355 Za

Zipovko ziv give Aa tuye iuv TPGOTyK Rgto RgOo Uai en dr hek ah 365 90 385 I 409 sSiu vag ovVa RYae for tight zhegoiuh5 iemotaig ud) ABzroguz 5vgoAga and for 10 415 biu Av Usa! EBe zeg Sub Zwab hai met nih si) Atia ve niv a 425 z30 ap ONia tugo tak ozip iu5 zhegoiieu beg iv Zag o rgo si zub 435 449 5 "azh: 58 "Vi" 315 "2ih" BILOK and . "-eiy" artificial sequence "RK "Ey" synthetic sequence: variable region of the heavy chain of the antibody lyse "KO"

"ERi" other signs "dya" KMNZ.. SY) V , and "823" Hava can include any amino acid, except heg "Vny BA pizza zhar ozip ivts o mai zits zee zi viu shiu ge) udi biy wgo pi siu iyi Z Iii iii iii zeg ieets dgo grec zek Sub aa led Bag obi be tk o RBe zago AVI tUg 20 25 za -iu hte nih tgr o Uudi Ak obip Aa RKO biu gu piu zv Bi: tgroma! 35 40 45 si tv Ii tak ORKO ABroviu pi tu tik odyar tuk div dr heg uv

Z 35 5 izhe Ru aAko vpe tak otie hek aia art tik Bek uh dep otvg AId tuk ta yaa o ivm bip met Aa Bek oivy aka Aia bij Ar otak ATa in tuk tugo Se 5 for a5 ia Aga aiz siu had tgroRBe led tugo tcrozi fight Yeiu so ivy Udi that 05 zh tvgomaf zer Zeg her5 "B" zha "ii u seii" BILOK . . "213" artificial sequence "Evyukh "Z" synthetic sequence: NUK-NI antibodies AKeiih); NUK-NI antibodies

A-RIBIIHI "Ei "E2iY" other signs "Va (3.3 kariya" Haa can pour soy any deacidification, except hak "a 5 liz siu hav tgv vne div tuk

From in: se yad "MO" that spa "FO" in "M: 1 sho "FO" in; "V" 16

"E12U BIVOKH "eyelashes" artificial sequence "DOK" hvga" synthetic sequence: variable region of heavy lachnuyea antibody a-hyZCYhU "et "E8i" other signs "om (3013... МН) Y I y "223" Hva can be any amino acid, blood yava "I ag zin Uvi shii yets ma) biz bek obi biu Biu vy ha dyin hgo ziuUu siu 3 Z 10 15 ek ivecch zago yivb Beg Su Aid A1ia ego bBiu Re tk o BBe 5vg ody tu

KZ 25 za seiu tiv niya tgroUai aku bij aZia RgoO shiu Ezhya SOIU ie biv teromai 35 40 45 siu tgrotie tng obi ap osiu ziu tuye zak o z5v tuye div Ahr ag ma! za va Bo iuz 5iu Agd RNe tng Ii 5eg aiv aAZo o tvg Zak ofu5 dai TVg oATa tag

Goths 7 75 5O in bij Mei av pdeg ie Aga A1ia biz Aza tn Aid Uvi tek tuk sSuya 85 ar 55 div Aga Aid sik hHaa tkr ore did tzhg tra si ziv obi tVhogen udi that 155 o

TNgoZhai bee ak "ayu 3 "t1i" ab "Fi" PROTEIN "213" artificial sequence "Ei" "ekh" synthetic sequence: heavy chain of antibody A-Y With mutant me e "I: p

Zichts zhai zip without ma? bis zeb o siu imu Oiu vu mai bij hgo Bi vih 3 Z 10 15 ek ivech zago yivb Beg Su Aid A1ia ego obBiu Re tk o BBe 5vg odi tu za siu Ta ni tgroudi Aga ozip aia wgo siu wuz bi iv sht tgroudi 4 cha siu tgroItIiv tk orKgo ABrosif Biu tugo so oAyavV tugo AT ar oheg ud! zova B iukh yshchiu Aga RBe tpgoIiv hag o Aiv aABrotng 5egoguzh Aa tVgoaia tuk 55 and 28 that igc o ziy Met abp zak oien AKYA Aiv o Biy Zo otak oAia ha tugo tk o sSuv as scha Z5

Aiia Aga ATa sih Bek iien ve diz tug tri bip shЮu TVgoiets ma! nu 385 o

Tvgozhai dek bek Aia ego tvg oyi b3iu Rg ek ma! Re Rgo and you Aa 115 i12a 125 rgo zeg Zag fu be tvgobZeg siyu biu TAgoAIid Av ivenosiu Suv and you ii130 1:15 15

Uai buh ABrotug RBa o hgo biv RGO mai tTVG omvi ego ter oAyap zag ob1u 145 i50 155 160 id ivc tvg za osi Udi nih tab oRBa wgo action Uvi yivu Bij zzu same z85 and i75 eiu vi tugo zekgoivb bBeg oheg o mai Uudi ts oMmaii Rgo zegobag zvgoi vu and their 130 si tk obei tVg tugo tiv Suh Aa UdDE to niya uh ho zag aa TK 135 that o iiuv vi AV Ru iuv Ua! Battle RgGOo rub zag Su Aa and TMKoNiv TBg 218 215 her

Sub vgOo o vgo buye Rgo did RgOo sats ivy hech bir 15 RgOo ego udi RBe 225 is VO Zh gai iv rye vgo Rgo iuh BgOo iuv a5O tBgoivy Met Ii zak Ak otvK o Rga 245 az 53 8iz chai te oSukh Ua! Udi mayi Azr Ua: Zakoniv bib AB vBko biv Ma!

In VE vho ich vne dp tgvV o tug Udi AVroviu Uudi ziy mai nih dv div j tIg g VE iiuv RvgOo aga sich bij vip tugo shiu bek otng tugo Ago di Ua! bug oudi 230 aa ME iv tngomai hec niv vip dr otgroivy Al Zi vu Bits tugo gu Su

З55 за зх зго июе жар зак Ap iv AIa ivtsi o Rgo Afa RgOo tiv bib y5 tk otiv Zee y25 З30 335 iuuz Aa tuz pi bip vgo aga sim RKO viv Uvi tuk o tvkogvy vko vga o z45 Z bvg Ag biv ot Mei tvgoiuh dev beep in Zegofen tvg oSuz ge Ua? 355 35 zo iu5 shiu ve tugo vko 5ek aBr tiv div uv biv tho biich ek apsiu 379 375 zv siv vgo siy Ap Aza tugo zu TVg o tBg orto Rgo Uvi yev aAvrobeg AZd 385 390 za5 dO siu bek vNe viv iets o tug ag oiyue ivm otak Uvi a5O oi uv yavg Akad tv 405 410 415 siv bip biu dyap Uvi Re hego buh ego zai Met nih biv ATia ivvonia 420 still ho aBpPONiz tTuk TE shiy gu et oivz beg ovo bek o Rga siu g u5 450 45 "Viy » sha «I «aiy»v PROTEIN «Vii» artificial sequence «ee «ВХ» synthetic sequence: NUYA-NO antibodies disidit); nUB-NI antktila d-gi8301t) "00" B div Ou tagOotgroRBe Aid tug y 5 kezOh 85 "eii" yiib "gi" VILOK "213x fat sequence "Ved "223" synthetic sequence: variable region of the heavy chain of the antitype

JSC

"NN: 55

Zina? ziv gen Uvi biy Bag obiu ziu Siu ep a! Biy vgo Bi ih i 5 for their ego em dkd i2en obeg o sukh liz aiv hek o biu Re tygOvVbe 5eg o Ayap otug 2 25 ta si tiv kiz tgrouvi Ago bBip aia vgo biu Uh shi gen siy ter ud! z5 35 45 siu tgrotiv so ovBgo dar oviu dizh tuye tTagoAyarotuk Aid Ar oZeg ha?

In 5 ich shiu vka RNE tr otiv chego did aZotnkK ag u dev tv A. z iuh iu vga RNe tvgoiii8 heg action ABrotyg Zeg buh dev TVg o ATa tui t 8 VO isp zip met a5p hek oivy Ag div ich ABr ot ATa mvi tuk tugo Seh 85 20 95 virgins Aga Aid bi tvgotgv vve actions tk tro obi 5iv bsiu tk oiek Udi za 105 Io tik oudi zek vek iiih "2305 6 "iii" 115 "Va" ILOK "Ж" artificial sequence "ik "Eva" synthetic sequence: variarel region of the heavy chain of antibody d-difference "Oi" BE zZish Uaf iv hech hai bin zek ziu Bius stu ivu mai biy Bgo bi u i Z ib ih zek ivy AgO Ben zeg subv Aia div zag osiu vNe o tag vva order give tUg «o 85 Z zi tiv vih tgroudi aga vip did go Bu uz Zira ra: YeiTE tgr Uudi ee 45 s ih tv oITv tngoBiu a5a vih ziu tugo bek o Avrotuk Aiya Avroheg Udi zi 55 bo iz biu aga vMpe tk oti zago doy aBrotpg o beg guh dhv otv did tug isp zip met a5p zak oivy Aga div ich ABrotK ATa mvi tuk tugo Seh yo cho at "iz Aga div viu tvE ter vve div teg otgrovie biv si teg ogets ud! ia 105 Io

Tygomai bek zag herykh "20" vu "ii" aa "Viy" BIVOK "ey" artificial sequence ke "KZ" synthetic sequence: t1951-heavy chain of antibody AKVOYH) with mutation ke "gi" other features "gv2x (B).. SNY) Y "gE3"U Hva can be any amino acid, except for zak km By sin Ua? biv hetsoUai Bin chego shiu Bi si ev o uv sid Rg bi siu y from 19 i5

Zeg om Aga vu ozegosSzhe ATa Aiv o beg siu Ra tVgb be bag oaABA otug siu thie ni tkrhoha! Ago siy Aivo Rg siyu uz bi viyu tkroma! 15 85 4 siu tk oti tak oRgGOo dvrobiu Bim tuk tvgoABrotug AT OR Zeg ud! 5E that izh5 Bi Aga RPae tvg oti zag oil de" SO uz Ah otnt o AiV tuye shcha ta T5 iesz bip Mei dya bek yin Aga ATa si) ar tvg aiv Uaii Tug tugo sSuye heh that Z5

Aia aga ATa sim Hav tgrovne action tugo tgo otu bipobiiu tagoien ma! is SCHI o tTVg Oma! ZegoZek div zZes tnt oi uz bi wgo bek Uvi bbe Rg ie div 115 i20 125 vgo BEK Zag oguh zak otv chego siu Bi tat oAiv Via ieco zi Sje vy iz 135 i4a

Mai uz ABV tTug Re go Bin RKO ma! Tvgozhai Zagkotkv dm Zac clothes 155 U i5k i«0

Aiv gen tyag obeg biu uai niv tBgovye rgo Aid ma? fen siy Zgobeb yii55 i79 175 siu vy tug bek oivu Zeus ego Uvi Uudi tyagovi vBgo Zeg ZvgozZeg oi vy yiishchi ih t9o siu tk obiv tk otuyeb Ich11i8 Suh azp o Udi dep Ni Guz ha Zvgodyavp tig i55 2 205 izh5 ma! dav gu ziuB udi bi) rgo iuz Zag suv a55 iuh tVGONiV TIig 210 2i5 28 su ego veGo Suh RgOo dia Rgo siv) iey gvy bi bib Bgo 5eg o Uvi Re 225 "V 235 MK ivy Reego rgo and Rgo zu br tiK oivu Mei tiv Zeg aga tvg Rgo t4x 250 225 pizza zha! so osuv Uvi Uvi ud)! Abrosha! Begonia sat der RKO vyv ud!

KZ KO iv vve AB tTge tuye zha! Avrobio Whoa! biv uv niv da A1a and tik dv VO 2855 iu vgo Aga biv bic vi" tugo bi ego tVgotuk zga ud) Ua: bek hudi 250 2955 shchi ivy tvgohai iv Ni bij zr o tgroiets A5p shi uv o bich tugo gu Su 3o5 330 | z15 Zy iuz mai beg dp iv Aa ivu rRgo ATa wgo tiv siy oiuvz tb oti hag 325 335 3335 iUuz Av iuUuch Shim biv who dko zin Rgo zip ma? tuye YES oiets ovgo go

BAZ zaz 35a vag aga siy bis met tpgoi zh dep siy har ek oivts o tyk pub vy za! 355 BO ia5 iiyuya Siu Re tugo Bgo 5veg Ar I1ie Aiz vi schi tov o sbits zegoahp siu 7 zu za ip vgo iv a5p Ay tugi jia TyBgotne Wga vko Uvi vy Ar bek Ar zy5 VI 5 Yad -iu zhvg Re vBye yn tuye beg iuz yeez tTVgoUshi AyaV iya ego aga tho

ZI 315 step biv Tu Ap mai Re ego buh chegomai Mei niz ziv avia ivy niv aga 425 435 dep oNnia tTuE TNK opii rukh 5egoivetsy zvgoivo) bek bro dim i uh 835 dai 4435 "VO" Ba "Ii" ab khaiaU BILOK y . "233" fat tracking "EV . Y. Y. And "Vi" synthetic sequence: Idsi-heavy chain of antibodies A-21501X) with a mutation of Mokh svv "rai" and signs of "g" SIRKO "223" Xa can be any amino acid, except for zeg udi biv ek obi bi BiU ep Uvi bij Rgo vziu bi

Э 5 В 15 shheg gez Ag geo obeg Sukh Aaia action begobziu Re tTVs RN bab o dyap tuk 24 25 3 siut tiv nih tcrohai agfoshiv action rgo biu vu Siu ev obich tcromai i5 I 45 siu tgroIiv tvgoZiu a5a zi Biu tugo Zek dyar tuk Aa ar oeg uv zo Za 5 iu5 BIiu Aga RBe tpg tiv Zeus aid zo tvs check movement ABYy tTVK o АЯa tu

Oh ta Z o iets biv met dyak ov AK oaid Bi OR otak Adi Uvi tuk tugo Seh 85 shcha z: aia AkO Aia biu Haa ter RA Aia tzhgotgrosiu siv biu tvgoivy Uvi 105 vo

Tig Uvi bek zek o ATa Beg tvkoiu5 biu wgo beg oudi Be ko ieb ATa herykh 120 125 vgo wag bek gu Wag o tvg ohak obi biu tik o ATa Aid iv biu suh i vu 130 135 ate

Huh? fu Avrotuk vBe Rgo ziy RgO Ua! tTnchkomai 5ek tgr ap ego viyu 345 i5a 155 iB5O dia gen tik obeg siu Ua! Ni tk Re RKO Aid chi ivu siy Zvgozehg 15: her 175 pi em tug vBeg o gvc zvgoBee uai uv tvgb o Uai vga 5eg hek Bag oi vu i8O 185 tb piu tygobiip tvgotye tiv Su5 av Uzi ABlloniv gu RgOo ZK ABY OTG iiz5 o o iue zvi Aeriuv iushch cha! bin Rgo iv ak oSukh Av uv tvgoniv tVg 215 rah sub Rgo RGOo Su Bgto Aia wgo pizza iec i viy eiu siu vBgo Zee mai rve iz Za 285 2855 ivm vne vgo Bho iuvz Bgo i e5 Ar o TK EM Mei tITE zhZek dgo tvpg ogo zav 255 a pim mai tp sSukh mai Uudi ma! a5r Udi chek niv bi dvrovgoa pizza ma! 250 25 Hey iu5 Re azpotgrotuk uva! ar oshiu Uvi Bim ota! No Aba Aa tooth tBg iz vo Tk5 iuvye Rgo agd biv biz shiy tuk o bizh ego tvgotuye Aga Uvi ma! 290 255

Zo05 Z zi5 325 iuz mai chek A5B iuch Aia ivn rRgGO Av vgo tITv Bib zfuv tvgotiv bek 325 335 335 ziyuya vid iv stu shi wgo Ak biv ho bip Uai tuk tTVs ov) Rgo vKo 340 345 v 5zevg aka siv bic Met tpgoiue demo bib in a short time ts oSuv giets ud! 355 ZO zv5 rukh s1u ne tuk Rko Zeg ahr o I1ie Aza Uvi ziv to Bits zegoazpobiu z 375 zva siv wgo O1Ch dya" aa tag oi TVgOTNGg o wgo Rgo Uvi geo Ar obeg 5 і85 EI 355 that spiu zak ve oiac teg ohegoiyue iem oh tayg ovi ABroguz yavgodkv otogo al Zi5 siv biv Tu ab» Ua! Re chego suye es tai me: Niz biv Aia ivu NI zva 425 45

Azp o niya Tug TVyg shii bue begoieYi bek oivy ego vBgo siu uv 435 40 345 "ve Va "21i" 445 "iii" VIiDOK "11" artificial sequence "280 | and "223" synthetic sequence: Idsi-heavy chain antibody lysibit) with mutation

MmIzte "or" wa si mai biv wu Ua? bij chego ovi Biu Biu gen Uvi siv vro piu viyu yi 5 10 15 zegoivy du becy zvkoSu5 liz div Zeg ziu ve tVg obme vag oayai tuk viZ Ii niv tcroUai Aga sip Aia RgOo si uz bi gc Bib teroudi 35 cha 45

Z tKr tiv tk orKO Arsiy biu tuk tvoAbr o tuk ATa ABYu bZegoudi za zi VO iv biu Adgd o vle tvgoiie Bveg o АЯa OR tVgo5ek rub Aa tTpg Aid tuye 55 and 75 80 ivy sip mes dey zak oivy aka div sim A5V tag o aid Ua tuye tUK sSuyeh a cha ya

Aia aga ATa spiu tv tgrobne action tuye ter obtu biv si TVg oi vu ha? their ip5 tr tTpgG o chai Zeg bek Aida Bag otpg rub biu vgo Zeg Uvi Be Rgo iv div i20 125

Bgto zag Yavg movement 5eg tpgoBeg o viu sim tk ziv AtTa ge) bi Sub iv 136 1:25 ido

Wow! Iuz Azr tuye vpe vBho biyu ho Uvi tvgoma! Zeg tv Aza Zag osiu 345 ho 155 yiv vis sez tk obBetg sib udi nih tik Re Rho div Uzi eets siy Begozakh yiv 175 175 5iu geo tuye zak oietsi zeg bek o udi Mai tvgoUuvi ga bevgoZvg zeg oyi vu i850 185 Ii siu tvgoBiv tagotUug Ii sub Am o UVi Azp No iub5 RGO Begodep OTG iz5 gm 205 iuz« Uai OR iuz gu Uzi zii RgO i uv bek osSukh ver uv tk oniz tk 216 215 y

Suz vgo Bgo Suz go Aa Rgo bii ievch gets bi Biu Bgo zZegoudi Pe ag 230 KB aa ietsy vne RgOo RgOo uh RO g b5 OR TVGOobets met IT 52k AgO TVgOorGa azh g 5 zZits zhai tk oSuz maii ma! ouch! A» uUudi zeg ni bin or o Bho Bin: Wow! luck "5 tu and vna ah otgo tugo Udi der obi Uvi bij Uvi ni Ap viz rub TK

In ko 285 it rgo Aga zi" Bi bij tugo bi Zeg o tvgotue aga chai Udi heg o Udi 290 295 zo iem tak cha? yev nih bip ivrotgo ivch am bi ziyu5 ziy tugo gu sSuv that EV 315 zga iu5 har Bag AZp gu Aid getsu ugo iz RgOo tiv Bits vuh tvg o ITVv chech 325 336 315 iu5 ATa uv vu sip vgo agfrsziy rgo Zip ma? Tug tTBR oi vu RKO jaOo 34 zach o zZek Ago Zib biv mmei tpgoruz Azy ip chai bek oivc tag oSuz iv Uvi z5h zo za5 iuz BIu RBe tuk RgOo bZet dhr IIV Aia chai biz tgroziv zeg dp stu

EN. 375 80 step RKO Bits AB AyaV tt Ou TBH oTNg o RHO Rgo xZi vu zr ohetg Aho zo zo 135 305 yiu zah RNe vne hec tugo Bag iuh yeecch o tvhoha! d5riuh zag aga that

405 z16 415 sip vip siu AYav Udi vve heg o Suye zek chai Met ni bid led iv nta i 425 azo dvy niv tug teg obip gub begoivu Zeg oivy beg rko bi uh ah 4435 "45 "Ah 0 "21ih 846 "2i2kh vIilaK , and "their artificial sequence "А "а2Ж" skntetic sequence: tidei-heavy chain of antibodies A-2KBIOZHTU with mutation Ч2ЗИС "В В зии hai ip gene Uvi і Zvhosiu s1iu оту гец ха! biv Rgo vie o1u i 5 10 15 zZeg iivy Aga ev bab ost Aid ATa zegoviu vbe tk ovBve beg o lava tuk

BO sSiu hie niz tgroudi aka ovipy did RgoOo ziu gu5 Bi ate Bich tgromai

From 5 siu terotiv tk obi ap o siu bi tugo deg da tuye Aid Akhrozvk in siu terotiv tv o5iF Ahp osi bi tuye deg Ahv tuye did AkhroZvg ha

For 55 re iu5 shi Aga o Rre tTVgotie Zag Aiv8 OR tNg oZeg gu dep otpg o Aia tuye shcha 70 75 va iv Bii Mei dp o 5eg iv Akad AiV ziy OR tTVK oAiv Udi tut M Su 85 zo V

Aiv aga ATa ziv tab o terovyv ATa tuk o tgr stu div bi tngoiyu tea still 05 i3o tTVg Oma? seg zak dia Bes tpgoiu5 piu vgo beg udi Re vBgo iv div 115 125 125

RKO dak obeg uh bab otvs ego vi piu t OATa Aid yiv) bi Sub i vu 130 i35 1

Uvi uz Av tuye Re vgo siy Bko Ua tvgomai bek ter Aa Be shiu 145 i50 155 iBO did yiv so oveg siyu Uudi niya tBgovbe vgo did UZ! iets b)iy bag Beh iB55 iuUp 175 si hemo Tuk beg ey 5ek Zvgomai ma! ts Uai RgO 5vg bek begog vu i8O 185 zho siu tvgosivay tchk tuye Iiv Suz Azp o wai Ahp NI uz Bha deg odyay TK

155 Re 2a5 iuz chai 45rviuh iuv ma! fight go uh heg Suya Azpoiuz tygoBiya TVg 210 ih 2

Su tu RKO Su RO ATa wgo iv iets okem obi siu vKo 5egoUvi vre 225 2 235 ee ietsn rRBae vKOo RTV ge GO i uv OR TBg o Benz Met tiv 5Zeg AgYa tpgORGO for 250 255 i-in zha! TNK oSuz mai ha! Ua) Ava mai begonia ziv azvorgo iv Udi 258 255 TO iuz RBa dB tgrotuye zha! aA5rosiu Wow! bin uzi niv dyap Aid iiu5 TVgG 275 280 285 from RGO Aga si ziz siy tugo oviu beg tng o tug aga a? Wai et ma! that ah Vk im tk o Uvi ivts o miz bij Art tgoroiets vaz bir uh shib Tuk oi uh sSuz zo zo ЗИ5 2 iuya UI bek AZp fu Aia ivy to Az vKOo hIIv sf: iiy TAK Iii Eg ze z50 335 iv viv vuz Biu sii vgo aga sii vgo bipozhvi tuk tvo) va RgGO z4a 245 350 ek ago siyu bin met tpg oi u AB shii Uvi Zag ofivm tvg oSuz ivy di 355 50 Za5 iiuz OTU BNe Tuk Rgo zvg Ar Ii AZv Uvi ob tgr bin beg adhp o biu 370 175 zva sip vgo bich ABV Ap otzhK rukh TVKOTVg o Bgo Rg Uudi ate dr ocheg to them in 5 to siu Bag vyv vne gam tk hg oiu5 iets tngomai azvoiuz ego aga tgr 405 410 415 ip osiv with Ap o mvi Bpye Zag oSukh hek ouvi Met niv bis didivy NO aha 425 aza ahpoNiz tug tag biy yuuz Zag ivts heg ben zach Rgo Ye1u uh 485 ve Z45 ki" I "lashes" 37 "ey BZlOOK "eiiz artificial sequence kggOh kegye synthetic SEQUENCE: KOoNsensuyu NUV-NI

"a "gi" other signs "Ai" y4r..8 "22Х" Had is Rgo dba Biu "vh "gii" other signs hikaz 15.53 "teZ" Hav is Azy or ap "VIKU "gi" other signs "dah KU. "283" Khhwa "k tpgovOZZz cheg "Y xx Ui tev oti tiyg hda Had o ziu biu tu Khaz Ap otuk did Avrozhaeg tai gud i z 15 i: 51u "eV 2 "eSchiyi" y "iy" BILOK . , "IZ" artificial sequence i "23" scnthetic possession: cosenses NUV-NI SNU "KU "gi" other signs "VU i3M..133 "283" XxXva " any amino acid, except o Zag "V AGE "vi" her sign "give 143..143 "22X" Had is tgr or g ets "Ne g did Biu Hna Ha RYB Had tug ii 5 "eV" I keiih 7 "Fig" vBIVOV "IZ" artificial sequence "aEOx "23" scnthetic possessiveness: covsensues NUV-NI SMT "V AGE "vi" her sign "give 143..143 "283" Hkhva "k tgroaov and you "Ne U did Biu tTpg Hav RIV Aid tug ii 5 hai y "her 9 "kii" PROTEIN "Ii" is an artificial sequence and "ReZ" is a synthetic sequence: it corresponds to NUYA-E with "Rec "regi" and the sign "Rai" of IED. "223" Hav is Zvg aba tuye "Koh "22i" other signs "Rep" SEU. khERi" Had zh Rga or diz "VE "riyu other signs of punishment TR... "veEa" Khav v Bga ayo tys "ayu y ip sip hHav teg o tBgotpg ohHva Had Te i 5 ch«eiye UZ "vii" 214 "VI » PROTEIN "Rii" hand sequence "22oh I "228" synthetic sequence: light chain of antibodies d "Ob" yav z hiv bii Mei tk obip ego ortho zegoveg Ben zheg Aid ze oudi biu ii 5 ei 15 ahr aga cha! tb tiv tygoSuz Aga Aa zeg osiv dev ouyai zvgotvg Aza 2 28 30 "di Aia tro tuye siy ip ish vBgo Biu uz div Rg vuh yivu ept tiv 35 0 45 tuk zag Aiv bek Be ivy Tuk hek osiu Uvi rko bek aga vve begosiyu za 55 bo hvgobiu chek z TVg o ar ovNe tBgoietsy tvagotiv bek Bag oiets pip rgo that 7O 78 SHCHI sii d5o vva did tygotzht tugo was siv ziv beb tugo Tpr otTvK vgo rgo

WHAT Q5

TNhorche stubiv biu tBgoi from Uai sim tiv gu ag tpkoUdi Aia div io ts 115 rgz General oma1i ra tiie vype o RgOo vBho zagzroviv biv gen oiiuz zak osia 115 1205 125

Te AtTa bek a! hafi Suh ate yen ab dva vVe tugo vho Aga ozin Aia 130 155 ia it ma! siy tgriuv Uvi der azp olia vu bij zag ozi ap ohetg o Biv 345 ho 155 iv bZim zag ma)! tb osiv bip der ozek yuub Ar bek o tag Tug bak oien zZeg 155 i70 355 ces tat oivtsi tVgoeets bag oie5 ZV o AZO tuye ziv gu Ni uv Uudi tu yko 155 195 aia sSuz ziy Ua! tBgoniv bij 5iu ivu beg zer orga mai tTVgogu cheh 19535 SCHE 25 vne Azp aga si bin Seh 210 "2302 76 "31 214 "T3y" Protein "IZ" artificial sequence "eV" "you" synthetic sequence: light chain antibodies A- " Om V

Azr tiv sip mei tygosip Zeg o Bho bZvb o zekofien o beg A)ia Zag oudi u 3 5 i5 ih ahv aku mai tk oti tpg oSzhe Aga o Aiv beg shiy Av ouvi zegotvg Aiv o Z za chai ata tgov therefore siy shiy gub tu shiu uh od kgo gu yivu iv o IЯa 35 40 45 ttg Vag Aia zhhak RNE isets tugo ego biu udi Rgo eg Aga Ra hetg o iu 50 5 bo chego biu beg shi tyg o AzrovBe pagoivgcs tyg o tiv bego5ek gen siy go 70 73 BO seven choir Ve Aia tyg otut tugo was beepoviv beb tuye YES otvg o vko vo 85 cho zh

TVGoRNe vi bip o siu tpg oz mai viv tiv high school Aga tBgoUuai Aii Aza my 105 ziv rgz Zag oma1i rye ti vne RgOo Bgo odzb obi biv gen oiiuz zak osia 115 12 125

TVg o AiTa ZvgoUai ma Suv en iv dyap o dzp o vNe Tuk o Rgo Ago Bin Aiv 1305 155 i15v it Mai biy tgroiiuv chai der aA5poaia ivy biy bek viyu Ap oheg o biv

155

Bek otngogao tt oivets bek oi uz A1V Ahv tugo ziv iu5 nih iv Udi tuk 150 385 ia div Szh5 sits Ua! tvgonia vip obiu rey veg obeb ego di tBgoiuz5 zer iz Vk 25 vne ap Aga peak Bin sSukh

Io "eV yah kiih 7 khatakh BIVOK hi" artificial sequence "eVx "283" synthetic sequence: consensus nuv-nNi "EV, "vet: other sign "aviv 53).. I "223 xHaa is 5Eg oaba te "VR "221 » other signs of "ai" i8..8 "22i" Haa is tgr or 1 en "yuyu tu did Biu Hna Ha FISH Aid tug iyi 5 ke in "e1i15 "gi? PROTEIN "bi1ZhU" artificial protein "vah "283" synthetic sequence: alternating nUuV-Ni vntitil a, A-i, a-IST, A- a "nt y

Avpotug network level 5 "VZ" tv "Riz 445" 12 IiVOK "813" artificial sequence ka" "TEZ" sevthetic sequence: tdoi-heavy chain antibodies VIiiO1t) "Sniff UV seven a! siv gay Uvi bic web biu shiu Ziu grec in vip vgost biu ii Z 10 15 zeg fen Aga geo bek su aia Aza Beye Ru Re TB Re bag lap o tuk 20 25 for soiu tie nii tgor UZ! Acad osip div Rg Zi gu Biu getz bi tkromai

Е 40 45 (ish te Te o tvg o hgo dv dv siUu ie tuye tvg dev tuye did dv Zag chai sik terti tTBb ogo A5rosiu from tugo tvg dr rotuye Aid dhrobeg chai for 55 o iv biu Adgd o vle tvgoiie Bveg o AЯa OR tTagobek iu Ap o tvpg div tuye ta 5 vk ivy bip Mei dupozeg ivy or A1ia 510 Azo tv Aid hai tugo tugo Su 85 Za 55 kiv agoa Aid z tv otgrovne Aia tek o tgo OBU vip o Biu Tit oi web di ih ip5 And that tTvgozhai Begozek Hades vag otpgoguz biu vgo hab o udi vna rgo even div 115 at 12h

Wha zhk Wah obuh zak otvg chego shiu Bi tvgoAiv Aid Eve Bim Suz vy zy iz 10

Uai uz dyar tuye Be Rgo siy vBgo Udi tvgomai bek tro odyap bek siu 145 і55 155 160 divets tak obZekobiu mai niv tBgoBNe Rgo Aa Uai en biy ego Zekye yB55 170 175 s-iu Bey tug zar oiyeen zag oUdE ma! tagozhZhvi vgo zeg o bet heg og ey 18 185 IZ oiu tngobiy tb tuye tiv Suh d5p ud! ab niv iiuz Bra bvg abi TNK

206

Ka ziikh 22

Suzh vgo tu Suh ho diya go div yenoiets zi biu Bho BegoUdi ve 225 za 235 250 ivy vve RgGOo VgOo iya Bho yiuv ABr otTIg oi2eu Mei ti 5eg Aga tng org 230 255 si) Uvi tvgoSuz mai maii Mai Azroua! bek nih shibyu AV Rg biv Udi 265 az ie iuv vye azy tov otuk omai ar obi Uai ziv Uvinia dp o ATa in TYK ra 2860 VE iuz wgo dgYaa bin sib Bii tugo odzp Zeg o tvg o tuk Aga ma) chai bek o udi ay 255 za iviotngomai gad niya bij aa tkroivn Az shi uv bis tu gu Sat 305 315 ZU za zu udi ek Azp og uz Aida iv RKO 13 RgO Iv bib ru tVgotiv Bag 325 335 3335 iUuz Aiv uh shim biv Bgo Ag o bic Rgo bBiv Min! tuye tpgroivets vgo go

A zaz 315a zeg aga sich bi Mmei tngoiU5 dep siy Uai degogvu tpgosSuv and you Za? 355 35 355

Guz shiu Re tug vgo beg aBryu tiv ATa uai Biy: tgrosiv beg ABp viyu zUy z75 zi ip Rgo biv Ap dya tugo imme TK otak o Bga vko ai ivy dr bek Azr 385 ho ve i b5iu BvVg Re Re ivy Tug bZvgog uh iv tagoha ! ABV fu 5eg AgYa go za 315 4315 vip bij bi AB" Udi me Zag oSuzh ego mai Met niv bib viz iv niv "20 425 430 dep oniv tug TNK vip iuh vek oivc bag ogvu ek ovgo 53)u z uv 335 acha 445 keOh 5 "21i" 846 "212 BILOK "bi1ZhU artificial subjectivity "in "283" synthetic sequence: IhIdebi-nazhkin lannyug vntytila A-ZT5 NT "en": dO ii Ua! sip iv Uudi sid begobiu 51 bi bec uai ziv Rgo siu Bi 1 5 ts 15 ego iiets aga iv bZeg Suh Aiz A13 ego biu vrBae o tVgoORKe beg oder o tug

KU and Vo sik kiv nih tgo Uvi Aga bip ia wgo z vuh bik ev bich tcrochai

Zh cho 5 zZiu tgrotiv tv osi Ahp o siu b3iu tugo ego AzrotTug Aid dor Zeg mai 0 5 what iu5 bi dgd Re tvgotiiv 5eg div Ah tVg o zheg gu ABp tTagOdiy tag 3 te 75 what iets biv Meg Azpozhegogven Aga Az bin Aza tk o ATa ma tugo tuk o Suh 85 Za 5 div AGO Had o biu tib tgrovBe led tugo otgo bit ip bRu tnk oyi vy Udi nyu 105 IV

Tvgozhai dek bek Aia ego tvg oyi b3iu Rg ek ma! Re Rgo and you Aa 115 and 12a 125 vto chego zhhak ogud bek tvgoZag obi siu YES oaid aiv ien siu Suv gay 130 i3h ii and iv Ar otuk rve RKO with rgo Uudi tgomai bek tgr o dhp o zegovziu 145 і50 і55 tv ia ivy tb ozegovih Udi nih tvgoRBe ego AT Udi yiv iy Zvekozeg 155 her i75 si vy tuye et oiv bZeg hat Uuai Udi tpgomaii Rgo zegozag Zegoi vu i150 155 tai eiu tpg osiv tagotue tiv Su aBa ma! Aaloniv food RgO Zag AB TNK 155 VO g it5 Uvi Ar oiuv ih ha! Bin Rgo ru ego Suh dvroi in tTVgONiv TBe o 215 VO

Su5 vgo o vgo buh Rgo did ro sii iv hecp si siu Rgo ego udi vve 225 230 235 Y t40 ivc vye tu RGO tooth RGO iuh AZO TPGoivy met her ek dk tVgoOvgo 245 For 53 vii chai tb o sSuz mai Udi Mai Azo o Uudi Zeh niya 01 der RKO seven mai ini mihi ya7o iub vna AB thootuye Ua! Ar ovi mai pis zhai Ni dep o Aia iu5 TBg

ВХ vo ho iU5 RKO Aga Bin bits obip tugo ava Zako tvgs o tuk ago Udi Zhai Beg oudi ha 295 00 iets tBtoUai ren oniz biYip Ar o tgroivy Av SiIU wuz YeYin tugo rub Su za5 Zo 315 zav it ma! Beg Aby iuch Aia in rgo action ego hTe biv yuk tvgoIIiVv dec 325 iz her ich AiV guz Ziu vip Rgo AgyaYa vich RKO zip mai tuye tvKgoivy hgo hgo zay for 350 zeg Aga Bin sii Mei tvgoiuh Aza bip Ua? bZagobets tvhosSuv and ech mai 355 ZO za5 zub yshiu Be tTug Rgo Zvg Ar OIIv action udi 5ii tgr oBits 5eg dp piu

373 375 za iv Vko siy Av oase tugo zu TV TNK oRGO Bho Ua? rev Azroheg a5r 85 90 za5 a sik bek re viv yets tug Bek gu em tk Uudi aBr gu god AgO ter za5 a 4і5 ip vip bir Azpozhai Re det sSuv bek ohai Mei nia sic aia gen ni 428 425 "30

Azponiz tuk tb siv uz ego ie hegoivu 5egorga siu yuu5 a 445 da "a B "ii" a "vil" vilak "21415 artificial sequence "B30" "Her" synthetic sequence Evidence: 1051 heavy chain of antibody A-1 "a" BE ziv he sat down and ate" Ua sii zegobiu siu shiu geb Ua! zip bkoa su biu iyi x 10 15

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TV 125 125:

Rgo zheg bzeg movement -vk tyg obeg o shiu bBiu TV Aia ATa ivech o siu Sus i vm 135 1315 I mai ke Ar o tuk Re Bgo bin Rgo Uuaii takoUVv!i hek ter azp o Zego o1iu 135 155 155 353 div rep tvg BEK obiu mai niz tvBgovNe Rg Aba Uzi en bip ego zek ikh 175 і75 oiu gen tuye bek oivets beg leg o zhai Uvi tVgov)i ho cheg ag oi vu 1850 і185 155 siu tvg osiv tab tuye і118 Sub AzpoUVi AZponi uh go bag Azy Tig with VO OB iuv ma! Ar Buv uz Mai shi go yuuz zeg o sSuz dyarofuv TK niv tak 210 215 gai

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Ba ziyuz SOIU AGO RVE Tvg oI112e bek Aid Ar o tAgojek rukh azpotvg dia tuye a 7 75 that in bij Mei av pdeg ie Aga A1ia biz Aza tn Aid Uvi tek tuk sSuya 85 0 zZ5 kiv Ak vek tuk sgrai dp Bek wgo biu ak biu Rye dBrotuk to 00 105 yuyu siu siv siu tk ogiven in tVgoUdi 5vg BEK 115 320 "om 85 "vai" 422 "gi2U Protein

"233" artificial sequence of sv sRv3" rintheticiv prlipppitid "B" 5 ii Uvi siv without wai piz begobiu s1iu fu ge Uzi bip Rgo bit siu ii 5 JAK 15 wk oign o Ago rei ozek Su div ded begopiu wav o tes ve otv odiay zak at 25 for

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Aiv Aga beg ze Rga terozeg obi bis shiu Re ootu Met Aza o udi ter io0 zo siu ziv biu tpgoivc udi TB ochai bek chek 125 "Liu Wu "eyelashes" 122 "eiiv BinOoK "giiy" artificial sequence "Rec "reVM"h synthetic polypeptide "A" I ziv may ziv gene Uvi biz bZeg obi biu biu vu o Uudi biv hgo ziu bid 1 5 i2 15 -vk ivan o AKo ivro5egoSuye did dia 5eg shi Ra tVg o RBe YES det Ap

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Bass "RIZ" is a synthetic polypeptide, "a" In this mak biy yivu di bid zhegoziu biu siu enozhvi ziv Rga siu shiu ii 5 zo 15 chegoien Ago iv 5eg o Suh Aiv a1ia begoshiu RVE TV Ne tVgoheg tug to 25 za

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"AK VO siv Mai bij yiv" mai siy hvgobiu si Bi Rets UVI zip vko siu 5iu ii 5 i: 15 ect fen Agud is) Bek oSuz A1Yiv Aa yavg shi Re te vve o typgobeg tuk that 2x BI azrotIie niz tep ohai Aga sii Aiv RgO stu uz b6iu vu viv tkv Ma! 35 biu biu tiv beye o hgo did Azrosiu ahr o tvVgoder o tuk dia Ayayy bag hudi zo z5 scha ut shShiu Ag Rye tk ii god div dhr o tvgozeg vuye Ap otyg action tuye y to t VO ip bip Met ap Bekogie' agbd AZa sim der otyag aid Ua tut tUg Kuz 85 For 5 virgins Aha ABY Ar o tuk AvroMai Aga chego tai stu Zv obiu Met der tuk

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AZOV otie nii tcroUuai aga siy div Rto seven gruz biu you her tgrocha! 35 cho 45 biu shiu tiv seg ggo action Azroshik vho tVgoAyaor tug Aida Ap bek ha! 5

Z ta t 8 yeez bip Mei dyip bek oivy Agd Aza si) Or tae led hai tugo tugo suz shcha ZU div aga Azy achi tuK AbroMai Ago vne uzi stu jek zi Met der tuk still 105 10 tTgroziu bij siu tvgoieets mni TB oUdi chego bek 115 i2e "azh: In "Via" 327 "2ih" BILOK and . "hey" artificial sequence "RK "v" synthetic povipeptykh "Ve Z siv di biv vv oUuVi siy zhvgobih siyu bBiu vy zha! biv vgo shi 5iu i 5 18 her ek tey Aguu isha Bag osv Aiva ATa Zegosiu Re hek ochzai uz Ko Met tut met tygotgroza!yi to siy div rgo siyu uv bi svi viv tCrowdi! for for 45

Zevkotngotiv tgrotuk biy devg osiu TygKotTVgodyar o tuk ATa Ar obeg Ua!

For 55 ko zu shiu AgO Re tbk her beg div АBY o tTVgozek vuv ABA tTpgodia tu and 78 5 iz bipomet dey 5Zvgoivy Aga dia sim ayar ts viv ai tut tuUg buh 85 za Za

Aiv aga bvg ek o Rgo tTgrobeg obi seven bBiu Re bim Mei Azroma! then another 35 15 si vip biu tvgoivu ta! tvgomai b5egozheg 115 i25 "Oh 3 "Ziikh i22 "vii" viiLOK "Vii" artificial sequence "kg "23" synthetic polypenpty "Vo" 83 ziv mai siv yev in bii zag obiu siu biu geo ma! biv ho viu bi i 5 10 15 zeu i2ai dga ep zvgoSe5 did did Beg si re tVg obme tiv Zak de zo 25 za tut ma! Zeg o tgroai Aga siy div Rgo siyu guv biU ietzozin tKroma! at 45

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Ba 7a 75 vo iey siip Mei Ak 5egoivu Ak Aza zi aAZv o taK ATya Udi tugo tugo sSukh 85 zi Zh viz Aga ego Bek o Rko tegrozek siu ziv bfu Rpe sib Met er Uai tgr ia ih iv siu bipobiu tagogets uv tak o udi Bag Act 12:05 "2" 85 "23rd" 322 "Vii" WHITE "her" artificial sequence "ED" "3" syntatechnimMm papipeptide "Yake ah pim mak vip ivtsi o mai bij es biu biu shShiu svo o udi siv vga sii Ye1u 1 5 10 i5 zag ben ago ev be Suh Afin Aa yaegobiu Re tk ohai tig o vgo Meii 2 5 Eh; tag Met ego tgr Uvi Ag vip ATa o vko biu Uh shizh ev obim tktroha! 35 45 45 hundred Z U still tunic in t fr ih U oz OR. iy oche gai zeg tag oti tv otuk bij ego biu tVgotag AvZrotuk Ta Avrozeg ma! a 55 shchi iuh siu dga RBe tpgotiiv chego div AZpotapg Bekoeu5 dv tyg o ATa tug 55 go 78 that ivy 5iip Met Azp ozegoien aka AIiv Biy aa tk Aza mai tugo tuk sSuv

Fo 25 dia aga Bek bekye go tgroBag si biy sim Re bi met a5roUvi tgr

KO oh I siu bip osit tk ogen mi tvgoev' zhecoBag 115 i28 "io" ze "v" 307 "232" video "ii" artificial probability kak x keV" synthetic padltipeptih "a" 5 ar otie bii Mei tBgobii heg rgo Zeb zagin zeg did Bag oUdi ziu i 5 10 15

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Zeg o biu vs pi tab o Avr Yaiv o typgoiem tag ItITe ve bZeg o gva vii rogo gav 75 VO siv Azy vBe Aia takotes tugo sub bii obviv ego tuyu tvgotpg o vKko rga

Kk cha 5 ts ovve siu siv bij tvboiuz Uudi sim ti guh "TO" 95 "ih U "ih vTlOk y . "Eyelashes" is an artificial sequence

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Аба ожие бів Мат баб обій чет вго баг гви дог диа Баг оуди Фіу и 5 юю 15

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TV ovNe Bir oii shchiu tpkgoi i mai bin Iiiv g uv tyu 305 "ZO" OV "air e ShChR "aiy"v PROTEIN "Vii" artificial sequence "ee "Cattle" synthetic polypeptide "kV" ZV dertiv siv met tak osiv ego Rg ego ozag ray Bak Afda begoudi viu y 5 yuyu 15 dar Agp uv tk otiv tvgoSuz Aga A1a bek o bip Zeus tiv bvgobeg tuk t ha za ivy div tgv otUg BIV vip i y Rgo 5iu gub Hades gori ivivev iv IIV zo az tug piu Aida beg 5vg o dgo Aia zegoziu Ua Rgo zak oadgo pe 5eg oschiu za For what zag oshiu hegoyetu TVg dr o RVa tBgoivy tvgolfa ego beg iiyets vip Rgo gav UZ that si aA5ip vVae Aida tag tuye tugo such sii biv tug tuyu zag bvgoRgo an

Kk Zo Z5

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Tug bi Aiva chZek o Beg Ak AЯa Zvgobiu ma? rgo zeg Or Be ego viyu zo 55 vo hak viu ek zi tVgoABr vne tvgoivu TNK otiv zek zag oiets viy rgo 5 B ih vozhi: (I U M poka rik bukh SHCHI t xx s ev de. schi yaii d5r vve Aid tvg otu tuye Su beep o beep tTug gay beast ozZee vro tie 85 y y scha ak

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ТНг вла сфиу Бий осию твгоижз чай вич ти ой у је 15 "EE NM "Ey" NK "RVy" PROTEIN "233" artificial sequence "2 "vai" synthetic polypeptide "AK SE dvy tiv 5iv Mmei ts biy bek oBgo ego bek oivc bek ATa 5vgohai1i siu 1 5 at 15

Avroaga Uvi TNK otiv tpgoSuz aga ATa ek biv Avromai Zegk tng А1В 20 25 30

Udi miv terotuk viv bip ih rgoa si gub ATa vgoiv tver ivy tiv tyv 35 80 45 tug Zag AtTa zvg be ivy tk Zekoeiu zhar ovgo beg ak VVE Zeg otu zova BO bag obih bek o biut ts od) VVe tBgoiivo tvagoITe ego bab yvi beat rga

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Tig Aries bi bio Biu tpgoiyue ud! 513 хтив иух 1 155 "ХО" log "Ви" 307 "i2U PROTEIN , heiZ"U artificial peshlidovity "EV and "aB3U synthetic polypeptide

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Zag siu bek biu tig Ar RBe tigoiveu tTvg tiv begobeb yivu Bii Rgo

55 In 75 vo siy ABY vNe Aid tab tuye tugo Sub bij ip beg o tkrotvK o ATa vgo vso

In what 95 tb ovme Biu BIV from your Uvi bin tiv gu this 05 "Vibe sh "Ave Or "2i2x viIilaK , and "their artificial sequence "A "23" synthetic polypenpty "OK OZ azroIiv siv Met tv siy zagoBgo hek bug ogets ego Aa bek udi o1u i 5 z i5 dar aAgp uv tk oi1v tvVgobuv Ag div bek o siy dz» Uvi beg o tag aa zo | in and 30 teas Hades terotuk viv Bib uh hgo Biu uh ATa Rgo uz gen ivem tie z cho 85 here Bek dyy et vpe o ien tug zag obiu Uvi rga bek dgYa vne o Zeg o siu - 25 vo

Zegoshiu bek ОЙіu tagodyav ve tpgoiets tvgotiv bek chego ben bij vho shcha to 5 8 sing Aa o vpe ATa tvb tuye sukh zip o beep bek o Bme TVg Aid vgo Resh 55 Za a5

TC OvBe sik siv biyu tvgoiUubB VER siy tiv uh yi ih "io yi05 "giyi" ii8uU "ai2z viDOK y y "iz" artificial sequence kgEOh o . "23" synthetic plipepty "nih Her uncle lives biv Bet tvK bib et o vko bek bvgogan bek div Bag ovi shiu y at 10 15

Aza aga chai tv IT tk oSukh aga action Yavgo osiy beb tIi8 bek obegb tug 2 5 yir iz ATa tgr otukg bip siy yuuz Rgo siu gu5 Aia go iyue gGvtsivu IZ that 45 tug siu Aia ek Bag aka did zak obi hUai rRga beg Ag RVE Zag oshiu za v BO chego shi bevt pim tyg Ar o vBe tik oivy tBgotiv bvv Begoivv biy vgo

B U 75 5O he OR vl ATa te tugo tuk o Suz ip bip tuye bek obegye chego Rg and you 90 U tyk Ovna sie vip siu tngoguv Uuai siv ii g uh for 125 his 305 "21st" 305 "212" volok "213" artificial sequence "Koch "PHASE" smnteticV polypeptide "ayu 405 dar tiv bip Met tng bij ego bho beg chego yiv beg Aia Zegozhdi viu and B her Ko ah Aga mai tVg oti tgoS'5 Aga Aiv ek ziv Beg o Ihyv zZegobeg tug 24 aa 33 yen ATa tgrotuye siy sip g wgo bi Bu Aid RGO iv vu en IIV 35 tk ti Aid zak obeg aka deia ego shiu Uudi vko zak dksh ve heksiu

ZO i o zZvkobtu ego siyu TVg o dvrovVBe tvsoivo tygoIIV Zek o bvkoivy vii rgo 5 TO y ka sim ar vye Aia tyg tuye tek Sub syp dyi tk nih Beg o bag vVho i v5 85 schi z5

TNg Aries siu bij bi tvgog z chai biz tiv t uv tkh 155 "OM yipb "vii" 0 "gii" PROTEIN "Ii" artificial sequence

Bass "RIZ" synthetic polypeptide,

And" oh

Er OITe bij Mei tvgobip hek org Zvgobak oiets zeg Aia Zag omai ziu i 5 10 15 vo) ag Uvi tab otiv tt osuz agu Aia egobiip ego ti 5Zeabohet tur ik; ku Zo t 25 ZO ivy Ata to otuk biv sip gu Rg bi ish Aia RGO zub ivet ivts tiv 49 45 tut sZiu Afa ek ag aka diz hak obi Udar vgo beg o adkd vve ego shiu zo va Bo

Zv b5iu bek optu TNK Ar o Rve tik iv tTVgotiv begoZes ge bij go ah tyaz va bin aABo vne Aia tk tugo tug Su viy Zyy tuye ego beg hek Rez i vu 85 0 z5 tik oRBa shi ziv siu tpgoguv udi biz tiv yuuh what 155 "2" 107 sii 07 "Swarm" PROTEIN "213" artificial sequence "ecu "VZ" synthetic polypeptide "new 0 er live fight Mei tyg obip begorgo 5eg o 5eg ofen seg Aiv bes omai siu and 5 і0 ih ahr aga cha! TV b ti tyg oSuz Aga Aiya beb siv Zag o Iiv hegoZeg tug 2 28 50 yenp Aia tgo tugo siy ip iz Bgo Biu uz did RTV ih ivv ivc IIV 35 0 45

Tuk Bi Aida zek Zag ako action bZee vium ma? rRgo zZek AgE RBe zek clothes for BU 50 zak tu ek z tVg ar RVE TBgoivo tygoIIv zego5agoyeecch o sip rgo

YaZ to 74 that that Ad5o Rye Aida tag otut tuk Su vii ip tugo zeg zag bag go ze 85 I ZI Z5

TNE vna Rubiv si tvgog z chai biz tiv iv 1 135 "ask 6 "actions" 445 "eiiv BinOoK "gii" artificial sequence wes "RIZ" Synthetic polypeptide, "a" OV zin Uvi zip gene mai bin bek siu shiu si you Uzi bipovgo bi oih i 5 10 15 zeg ren ag in obZek Su diya Aia ek obiu Ve tk o RVe YaegodyaYy Tug y 5 KI; siu tiv No tgr Uvi! Agd biv ATa ko biu uz shim iev sim tkroba! 5 45 siu tgrotia tak obi Ap biu siu tuk zag o Azrotuk did AvroBeg di iuya Bi gad re tvK tiv heg div dep o tvgoak gu dev TNK oaia tuK

BU then what ivy shiv Mei Azy o shek gen aga div bit azor tag Aza mai tugo tuye Sub

Of what 25

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Tag omai des ego ATa Yavg tngofu« siu Rgo bvgoUud! Rye bho ivsh Aa 115 120 125 tu vak bek uh bag otv ego osiu piu p ATa Aivivo siu Sub g vu i55 135 ii chai uh Av Tuk vav Bho vi rgo Uai tgohai zeg ter Ahp ego vyh i45 150 155 IB zh ga ze - heka visa sh tn uU du Aid khz 1 ts i du visa em so obe viyu chai niia tab orRBe rgo Aid Ma! ivu bij bek oche: i55 470 175 si hemo Tuk beg ey 5ek zvgouai ma! ts Uai RgOo 5vg bek begog vu 150 155 Iza siu tvgosiva tchk tuye Iiv Suz Ah Uai Ahp NI uz Rga deg odyay TK ip5 Ya Oh iz Uvi OR gu iv ma! 5its rGO uv zak osSuv Ar oyuv TVgONiV TPg t 715 u

Suz vso vBgo Su vro ATa vgo sich hm oivo btTu Bi vgo begouvi Rre 225 238 235 ai ivy Re vga Rgo iv ha uh dr pVgoiem oMei tie schesg o dgd tagoRKo gas 250 283 siy di tak ossuh Uvi Ua! di dr ha begonizh biy dar vgo sii mai 255 KK iu5 vVa AV tgrotug ma! Arsi maf bitz hai niya abap Aid fu TBgG gu8 28 KO iz rRga aga ziv biv bij tugo aa ego tax otug ak Uvi di web Udi

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Number 355

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For ED 35o

Zeg Aga sich oits Mei tvgoi uz dp oBip maf Zeg ovben twk Sub gets ma! for 85 365

Tu 5iu Re tuk go 5eg aBr tIZie Aa har oziv ttrosits zaegodzp siyu

ZO 375 380 vip ovgOo Zits A5p aa tTuk gub TS OTG o RHO RKO UVai gen o ABr Jacques AhO 385 i9ts Zach BE: siu zZvg o Rbe VMe yen o tug ego oi uh iv) tagKoHai ABa fu Zeg o AgYa to

Zach 10 415 ip vip sih zp oUdi Re zag oSukh Zv mar Met niz ziv aid iey niv «ho 425 za

AEponia tug tVg obip iub5 vegoivy Bag rem Zag ovgo siu 435 a4o dach "Nu i05 "2Iih IZ "212" PROTEIN "RIZ" puchna sequence "Vg3x Syntetuchniv polypeptide "Kl" oz

Hvgoiien RBe div tuye o siu zhip biu Tgoivo ud! tVgohdi 5 sh "B" 11 "arias" BV huts BIVOK "Phys" stumna sequence "AGE "RIZ Synthetic polypeptide "more

Met sziu ttrobzek sub tiv Iyivy RE gay ma? ATa tk oAiz tvg action and Z iv 15 action tugo dyzii Uudi sip iv Uaf ovi) bZegobiu bit 5iu iviu ma! drink for

With them Z tu Biu siu zak iv Ag oiya begoSu5 div Ata ek osiv vya tVC riv z5 35 45

Zekg Azp otug siut tiv niz tk" in Ag biv Atia rgo sif iuz Tu and you

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Z cha BI tTgoATa tuk gets bij Mei ABpozeg ivy AgO ATa biv dar o tpg o ATiayaa ud! that 135 z

ТУг туг Сух АЙв Ага ATа bi вк им вве AtTa tuye tgr оби бий вих 115 и120 125

TEgoiei uv tik o Uudi Beg eg dia 5eg tak o guh 5IuU Rgo bag omai tuk 130 135 1

RGO ivy ATa Rgo ud Suv ziu az tag o tag o stiu bek 5ek udi TBg oyi vi 145 o 155 to bi Suzev omvi gu biu tug be Rgo sim vgo Uvits ve tygotkr i55 i170 i75 azp oshig si ego res b5eg deg siu bai nNib tygovye hgo Had Uzi and vm 150 155 nyu sip ego aABrV ren tug tak oivy Beg o Zek o Beg uaii tb oudi tpg bek Bag 195 z OB

Tezhotgarobko ek obi Yaeg tiv twkKoSuzh ayav Uvi Aza niz vgo Aia beg

WHAT 215 r vek otvgogu5 uai Ar gu iu5 Ii Sim vgo Akd shim vga o tvgoIIv uv 05 ho 235 tai

Vgoa Suz rta rgo Suz im Suye RKO dad vgo give Ben yiv vi bi vko 85 25 25 svgoUudi ve tiv Ra vBgo RgoOo iv tiv gU5 AYU UVI vi mes Iiv 5Eg

BO 255 RU ivy ego vta tt Ua TAK Su uati Ma! Uvi du UVI Bag in dr avo ka "Va 5 vgo AvpoUVi shiit iv est tgrorBa udi dya AVp Uai viv mvinia tik

OO 25 TSO

Aiv bij tvVgoshiv tab oniz Ag bij der tugo Avp o ek tvgofva dk chai zi0 315 U

Udi hag did Bec vga tiv biv ni sii dbYu tho Met ek bi g vi 330 tsik sho -kt- shko vyv gu5 Suv gu di dm o dyap i Uu5 a5V o iey RKO Aid vgo IYiv Biy aga z4a zah o tyk Ira bek zub Rg uh Bi Beg Uzi Aga aia vgo bip Udi tug Uudi y5zhh Zo z85 ivy rgo Rgo Bgo BIV sitz bib Met tngofuz uz ziv ma! tTVgoivy tvg ze 38 380

Suz Mei chai tBg o dr RBe Met vgo sich Ar otiv tus ma? bin o terotpk

Зк з ха5 зас

AB oA5P EUTU uh TVK o Zits iets dey tuk gu a5V tvgobits vgo Uudi iv zach "za "15 ah zag Azo viu Zag tug RBe met tugo beg oiuz ie5 Aga uzi iv i z

Yar 425 330 iuv dya tgroza!i Beach aga adap obeb tug Bek obSukh zak udi Udi Ni he 35 440 445 s iu fen nih da No No tTVKOotTvgb gu bek ovBve o zekg dgod tv ovgo pis zo 455 Z zi Met su tgrozek Su Ii khtiv ivy vpe o rec zhi div tvKodid tag aka zo PU zva

Z arniv cheg drotov bij Met tvg obi" Zagovuto Bek zako ogeey Bag 45: za "85 id zag oudi viud der Akd Uzi tik yi tvgosSuz dGYA dia zakobiv Ar hy 0h ziy chai vek tnk aiv Uudi did tgrotug sip Bib o yeuh ego bi izhzh grandfather rgo

Zih o 5I5 yuuz ben oiyets tiv Tug b5eg diya bZeg Ne iv Tug bek viyu Udi go Bek 530 335 Za dga fell o zet sie zeg sih zak osiu tig oder vve tvgoieeu tab tiv Bag

Zach zvo 55 BO

Zeg o hec biv wgo bi) Aho RBe AZiv togoOtuUug tug Su bij bip tugo tug 51 AF 55 tTvgotvgoAia tb otvEoRnav o biu sii viu tvgoruz mai sin tiv i hU5 Aga zna 585 ZU

Aa AB AЯa ATa bgo tpgoUdi ektiv Ree vgor rga bee zegobiv siy

Zah BO 5 iem tag back optu siu Aia Zeg za! in Su5 Byvoivts dai dp VBe tug viv vis B)

Rg uh AB oIIv dB Udi ge5 tgroiu5 tiv a5r o BIiu ze biv aka biv

ZO 235 vla ahp siu ma! yeets dey bag tgrotig o Azo biy ABr Zag iv der Zeg o tNg shІ5 zo 55 tuk Beg met zah Beg tyk oi Tagoivu tTgovguh AbV obit tk osiv Aga va vva tu

No dyap bek tuk tvhosSkh biv Aia tBgoniz gu TVgozZag tvhohak rgo bE5 BE 85

Hey ma! uh ek RME ABpP o AgGO aAZp OsTM su uzvah "Vii Z "eiih ih "gi2U BILOK and . "eiiiZ" you learn the sequence "Ek" "RES: Synthetic polypeptide "ope Z zin Uvi bip en ma) bi bek obiu shiu viu vy hai dyin hgo ziu

Claims (54)

3 5 10 35 FORMULA OF THE INVENTION 1. Isolated antibody that binds to Wadeid! of a person, where the antibody contains NUV-NI, which contains the amino acid sequence 5ЕСО IЮО MO: 35 or 78; NUMV-H2, which contains the amino acid sequence FEO IU MO: 28 or 36; NUV-NZ, which contains the amino acid sequence 5EO 10 MO: 55 or 59, where X is any amino acid except 5 or H; NMV-11, which contains the amino acid sequence 5EO IU MO: 38; NMV-I 2, which contains the amino acid sequence ZEO IO MO: 39; and NMV-Y Z, which contains the amino acid sequence FEO IO MO: 16 or 40. 2. The isolated antibody according to claim 1, where the antibody contains: a) NMV-NI, which contains the amino acid sequence ZESO IYUO MO: 78; NMEK-H2, which contains the amino acid sequence 5ХЕО ИЯ МО: 36; NUV-NZ, which contains the amino acid sequence ZEO IU MO: 55; NMV-11, which contains the amino acid sequence 5EO IU MO: 38; NME-12, which contains the amino acid sequence ZEO IO MO: 39; of NMK-I3, which contains the amino acid sequence of ZEO IU MO: 40; or B) NUV-NI, which contains the amino acid sequence ZEO AND MO: 78; НМУВ-Н2, which contains the amino acid sequence 5ХЕО ИЯ МО: 36; NUV-NZ, which contains the amino acid sequence of ZEO IU MO: 59; NMV-11, which contains the amino acid sequence 5EO IU MO: 38; NME-12, which contains the amino acid sequence of ZEO IU MO: 39; of NMK-I3, which contains the amino acid sequence ZEO IYUO MO: 16; or c) NMV-NI, which contains the amino acid sequence of ZEO IU MO: 78; NUV-H2, which contains the amino acid sequence 5ХЕО ИЯ МО: 28; NUV-NZ, which contains the amino acid sequence of ZEO IU MO: 59; NMV-11, which contains the amino acid sequence 5EO IU MO: 38; NMV-I2, which contains the amino acid sequence ZEO IO MO: 39; of NMK-I3, which contains the amino acid sequence of ZEO IU MO: 16. 3. Isolated antibody according to claim 1 or 2, where the antibody contains: a) a MH sequence that has at least 95 95 identity with the amino acid sequence of ZEO IO MO: 54, and an MI sequence that has at least 95 95 identity with the amino acid sequence of ZEO IO MO : 34; or p) the sequence of UN, which has at least 95 95 identity with the amino acid sequence 5EO IJU MO: 58, and the sequence of Mi, which has at least 9 95 identity with the amino acid sequence 5EO IJU MO: 10; or c) a UN sequence that has at least 95 95 identity with the amino acid sequence ZEO IO MO: 62, and an MI sequence that has at least 95 95 identity with the amino acid sequence ZEO IJU MO: 26. 4. An isolated antibody that binds to human daddeid1, which contains: a) the sequence MH with 5EO IO MO: 54, where X is any amino acid except C or H, Its sequence is MI. from BEO IU MO: 34; or B) the sequence MH with 5EO AND MO: 58, where X is any amino acid except 5 or H, and the sequence MI. with BEO IU MO: 10; or c) the sequence MH with 5EO IU MO: 62, where X is any amino acid except 5 or H, and the sequence MI. with BEO IYUO MO: 26. 5. Isolated antibody according to claim 4, where the antibody contains the sequence of MH with 5EO IYUO MO: 54 and the sequence of MI. with BEO IYUO MO: 34. 6. Isolated antibody according to claim 5, where the heavy chain contains the amino acid sequence zEO IU MO: 56 and the light chain contains the amino acid sequence 5EO IU MO: 53. 7. Isolated antibody according to claim 5, where the heavy chain contains the amino acid sequence ZEO IU MO: 57 and the light chain contains the amino acid sequence 5EO IU MO: 53. 8. Isolated antibody according to any of the previous clauses, where X is selected from A, OYUO, E, b, I.K, I, M, O, K, THOSE 9. The isolated antibody according to any of the preceding items, where X is T. 10. An isolated antibody that binds to human dhaddeid1, which contains: a) NMV-NII, which contains the amino acid sequence ZEO IJUO MO: 78; HME-H2, which contains the amino acid sequence ES IU MO: 36; NUV-NZ, which contains the amino acid sequence of ZEO IU MO: 37; NMV-11, which contains the amino acid sequence 5EO IU MO: 38; NME-12, which contains the amino acid sequence of ZEO IU MO: 39; ии NMK-I3, which contains the amino acid sequence 5ХЕО ИХУО MO: 40; or B) NUV-NI, which contains the amino acid sequence ZEO IYUO MO: 78; NME-H2, which contains the amino acid sequence 5ХЕО ЙЮ МО: 36; NUV-NZ, which contains the amino acid sequence ZEO IU MO: 64; NMV-11, which contains the amino acid sequence ZEO IU MO: 38; NME-12, which contains the amino acid sequence ZEO I0O MO: 39; ii NMV-I3, which contains amino acid Ko) sequence ZEO IYUO MO: 16; or c) NMA-NI, which contains the amino acid sequence 5EO IU MO: 78; NMUV-H2, which contains the amino acid sequence zEO IU MO: 28; NUV-NZ, which contains the amino acid sequence ZEO IU MO: 64; NMV-11, which contains the amino acid sequence 5EO IU MO: 38; NMV-12, which contains the amino acid sequence ZEO IU MO: 39; of NMK-I3, which contains the amino acid sequence of ZEO IU MO: 16. 11. Isolated antibody according to claim 10, where the antibody contains: a) the sequence of MH with 5EO IYUO MO: 33 and the sequence of MI with ZEO IYUO MO: 34; or p) sequence of MN with BEO IU MO: 65 and sequence of MI. with BEO IO MO: 10; or c) sequence of MH with ZEO IO MO: 66 and sequence of MI with ZEO IU MO: 26. 12. Isolated antibody according to claim 11, where the antibody contains the sequence of MH with 5EO IYUO MO: 33 and the sequence of MI. with BEO IYUO MO: 34. 13. The antibody according to any of the preceding items, which is a full-length Ids1 antibody. 14. The antibody according to claim 13, where the antibody essentially lacks an effector function. 15. The antibody according to claim 13, where the heavy chain contains the M2970 or M297A mutation. 16. The isolated antibody according to claim 12, where the heavy chain contains the amino acid sequence ZEO IU MO: 51 and the light chain contains the amino acid sequence ZEO IU MO: 53. 17. The isolated antibody according to claim 12, where the heavy chain contains the amino acid sequence ZEO IU MO: 52 and the light chain contains the amino acid sequence ZEO IU MO: 53. 18. The antibody according to claim 11, where the antibody contains: a) a heavy chain that contains the amino acid sequence 5EO IU MO: 69, and a light chain that contains the amino acid sequence BEO IU MO: 75; or p) a heavy chain that contains the amino acid sequence ZEO IU MO: 70, and a light chain that contains the amino acid sequence BEO IU MO: 76; or c) a heavy chain that contains the amino acid sequence ZEO IU MO: 79 and a light chain that contains the amino acid sequence BEO IU MO: 75; or a) a heavy chain that contains the amino acid sequence ZEO IU MO: 80 and a light chain that contains the amino acid sequence 5EO IU MO: 76. 19. The antibody according to any of the previous items, where the antibody is an antagonist of the daddea1-mediated signaling pathway. 60 20. The antibody according to any of the previous items, where the antibody does not bind human Uhadded2. 21. Antibody according to any of the preceding paragraphs, where the antibody does not bind 0 4 of a person. 22. Antibody according to any of the preceding paragraphs, where the antibody does not bind human 1. 23. The antibody according to any of the previous items, where the antibody does not bind mouse dadd2, mouse ri and/or mouse OG I 1. 24. The antibody according to any of the preceding items, wherein the antibody reduces tumor growth in a murine xenograft model without causing weight loss. 25. The antibody of claim 24, wherein the murine xenograft model is a liver cancer xenograft model. 26. The antibody according to claim 24 or claim 25, where tumor growth is reduced by at least 50, at least 60, at least 70, at least 80 or at least 90 95 AOS/day (TO19b5). 27. Isolated nucleic acid, which encodes an antibody according to any one of the previous items. 28. A host cell containing the isolated nucleic acid according to claim 27. 29. A method of obtaining an antibody, which includes culturing the host cell according to claim 28 in such a way that the antibody is produced. 30. An immunoconjugate containing an antibody according to any one of claims 1-26 and a cytotoxic agent. 31. A pharmaceutical composition comprising an antibody according to any one of claims 1-26 and a pharmaceutically acceptable carrier. 32. An antibody according to any of claims 1-26 or an immunoconjugate according to claim 30 for use as a medicinal product. 33. The antibody according to any of claims 1-26 or the immunoconjugate according to claim 30 for use in the treatment of cancer. 34. The antibody of claim 33, wherein the cancer is selected from breast cancer, lung cancer, brain cancer, cervical cancer, colon cancer, liver cancer, bile duct cancer, pancreatic cancer, skin cancer, B-cell malignancies and T-cell malignant neoplasms. 35. The antibody of any one of claims 1-26 for use in the treatment of a disease selected from asthma allergy, an autoimmune disease, a disease associated with goblet cell metaplasia, for example in the lungs, and excess mucus, comprising administering to a subject with cancer of an effective amount of the antibody according to any of claims 1-33 or the immunoconjugate according to claim 30. 36. The antibody according to claim 35 for use in the treatment of a disease associated with goblet cell metaplasia. 37. The antibody according to item 3b for use in the treatment of asthma, chronic obstructive pulmonary disease (COPD), cystic fibrosis and Barrett's esophagus. 38. The antibody according to any one of claims 1-26 or the immunoconjugate according to claim 30 for reducing the growth of cancer cells. 39. Use of an antibody according to any of claims 1-26 or an immunoconjugate according to claim 30 in the production of a medicinal product. 40. Application according to claim 39, where the drug is intended for the treatment of cancer. 41. Application according to claim 39, where the drug is intended to reduce the growth of cancer cells. 42. Application according to claim 39, where the drug is intended for the treatment of allergy, asthma, autoimmune disease, diseases associated with goblet cell metaplasia, for example, in the lungs, and/or excess mucus. 43. Application according to claim 42, where the drug is intended for the treatment of a disease associated with goblet cell metaplasia. 44. Application according to claim 43, where the drug is intended for the treatment of asthma, cystic fibrosis, chronic obstructive pulmonary disease or Barrett's esophagus. 45. A method of treating cancer, which comprises administering to a subject with cancer an effective amount of an antibody according to any one of claims 1-26 or an immunoconjugate according to claim 30. 46. The method according to claim 45, wherein the cancer is selected from breast cancer, lung cancer, brain cancer, cervical cancer, colon cancer, liver cancer, bile duct cancer, pancreatic cancer, skin cancer, B-cell malignancies and T-cell malignant neoplasms. 47. A method of treating a disease selected from allergy, asthma, autoimmune disease, diseases associated with goblet cell metaplasia, for example in the lungs, and excess mucus, which comprises administering to a subject with cancer an effective amount of an antibody according to any one of claims 1-26 or immunoconjugate according to claim 30. 48. The method according to claim 47, where the disease is associated with metaplasia of goblet cells. 49. The method according to claim 48, where the disease is selected from asthma, chronic obstructive pulmonary disease (COPD), cystic fibrosis and Barrett's esophagus. 60 50. The isolated antibody according to any one of claims 1-26, conjugated with a label. 51. Isolated antibody according to claim 50, where the label is a positron emitter. 52. The isolated antibody according to claim 51, where the positron emitter is 8972t. 53. A way to detect Chadded! of a person in a biological sample, which includes contacting the biological sample with the antibody according to any of claims 1-26 and 50-52 under conditions that allow binding of the antibody to the human natural dadde1, and detecting the formation of a complex between the antibody and the human natural added1 in a biological sample. 54. The method according to claim 53, where the biological sample is selected from breast cancer, lung cancer, brain cancer, cervical cancer, colon cancer, liver cancer, bile duct cancer, pancreatic cancer, skin cancer, B-cell malignancies і Т-клітинних злоякісних новоутворень Чаді люднни (ЗБОЮ МО) МАЗРЕТЕОВВавРОВЬСЬКИСАСВАКУСОАВООЕВІВІЬОСМОМУМНОДІЮОМОМССОСВАХ РОПВКСТВОБСОТІЕКУСІКЕОВВУТАССРОБКОВСОТРУХТОСМТЕМНЬКАВВОМОВНАХ УБРЕВЕАМРЕБУТСЬТУКАНОВЕМОТУОРОБІТЕКАВНЕОМІМНРАВОМОТЬКОМТОУАНЕВ ХОТНУТСРОХХУСРОСМЕРСВККОрЕКаНХУАСПОМОМЕТСМЕСНМСРЕСМЕАТСВОССВЕ КНавскрРООСВСОУЧМОССУСЄРТКСІРНРОСУНОІСМЕРНОСЬСЕТМНМИОСОСОКрЬНУЄ СРТНОРСІНССТСВНТОРОКУОСВСРЕСУВСРИСКІАЕНАСЬВОРСНМВСВСКЕТВКОКЕС ЕСВРЕОУТОРТСВТМІПОСЯРММСЕНООТСОрРІСУМОРКОУСВРОВТОКТСОСОАМЕСЕАКЕ СсУМАКЕСКНЬІВБУХСОСЬРОММООМСВІВІМОСЬСОСОМОВВСВОСУВСУВСІСВВОЖА СОНСЕВОІВЕСАЕМРСІМССНСОМЕІМВКОСЬСРТСЕВОМСОБОТОУСЕРИРСОМОВОС УМНКАБРУЕСКСРЕВУВСКИСЕНСКОВСВТТРСЕУТООСТУАМАВНОТРЕСУВУЇВВНУСО вНОКСКБОВОсСКЕТСОСВКОовТстТІСсНеМІВОСЕВМРСКМНОСТСІОСУ МВУКСІСВОСНЕ паАХСЕТМІМНОСВОМРСНЕССТСВрІУМНОКУСОСсКЕМСЯКОоКТСиВНОВОСОКАТСВКОЕС тТОЕСПАЕКСМСРОСМВСТТОМІАННОВСІРМРСНКССТОСУУМСЕВЕТСУСКЕСМЕСРІСА ОМТМОСаРНРСУМВОТСУрарМиуВСсВСАВОЕАОРОСВІМІМЕСОВБРСАКОАТСУрВІВ СУКСУСРРСНВСАКСОБУВСВРСІТМСЕЗІРОСАКМОПОСМРСОСіМСВІДСяКУЧСОВЕ РОСБОНКСНЕАВСРЕСОНСІРІПОРОСЕНРОТОУСЕСВЕЕВБОРУКТЕСТВОВУХОРНСЯМ ІТЕТЕНКЕММОРОЇСТТЕНІСЗВОВМЕМІІКИУЗАБУВІХТАСЕРОРВАВМНЕТНУВІВАКО ІВООСМРІКЕІТОКІТІОБОВКНОСМОВІІААУАЕУНУВАРІКМВТОКТУРІЬВВУВТУД ЧІССЬУТАКУНСЬВКАВКРСЯВТНЗАВЕОВЕТНМУККОСМОТКМРІВКНСАМТУРІКРЖЕ МЕМоКМаКІНТНИЧЕУВЕПОМОКНООКАВКАКОРАУТЬУПВЕВЕРРНСТРІКНРМНИТНКО переве ОяЬНЕМЕХТУ чЧаді миші (ЗБОЮ МО) МУБРЕТНІВРСКРЬБІЬАТЬСАІВАКУСОАВООКЕТ ВІСВНОМУМСЕСОМОМСОСОЧНИ БОрВКЕСТАОБСОТУРКУСІКИХОБВУТАООРОБРОБОБТВУХООМТЕМНЬКАВВОМОВМКТ УБРЕБЕАНРВЕБУТЬІУКАМНОВЕМОТІОРОБІТВКАВИБОМІВРЕВОМОТЬКОКТСТАНКЕ ХОХКУТСПОНУУОСЕССМКЕСВККОрОККснуУасСпОМОШКТоМЕСНМСРОСнКаІСНОССЯР квавскиьворовосоханосьхсокостенрОСУНОТОЦЕРНОСТСВТВНСООЬСОКОСМХЄ бтТкОоРСЬМАСТОВЕТОРОКХУОСЕСРЕЄХВСРМСВІДЕНаАСЬСОВСНМВОВСКЕТОВСКЕС ЕСЕРОЙ ТОРТОЗЕМІРОСЕРМКСЗНОСТСООСУМСЕКСУСВРОМТКТООБОАМЕСЕАКР СУМАВЕСЕНОХТАБУУСОСІ РОКМООМСВІМІ МІК ООСОМОАОСВОБУМОХВСІСРРОТА СПЕСЕВОІРЕСАВМНРСЬКИСНСОМЕІМВЕОСТСеТОр ВОМ СО Ото ХСсЕРНвСОМОовОС ТМКАБПУЕСКСРЕрУКОКМОВНІКОНСВТТтТСвУТОВСТУАНАВМОТРЕСВУІВВМОСО РИСКСКБОБОСКЕТОрСНКОКТСТУСНЕМІМОСЕБМРОКМОСТСІОСУМЕХКСІСВОСКЕ САБСЕНМІНОСБОВЕСНУССТОВРЕУМОЕУСрСКМсиКОК Тс ВОСВЕАТСММСС В тПЕУОрТЕКСМОРОСНЕОТТСВІАВНЕВСТВЕМРСНМОСОТОУУМОрВКТСУСКВОМЕОРІСТ ОКТМрСВРЕРСУМЕОТОТРОрМНІВСВСАРСКАСРОСКІНІМЕСОВВРСАКОВТСТНВІВ СХОСІСВРОНЕСАКСНЕУВСВВСІТМСВУІБОСВЕМОПОСКУСОСЬКСКУАСВЕУМСОРВ РОБЬНКЕНМЕСРЕСОВСІВУТІООСЕУВРОТСУСЕСВЕОБІСРУКТЕСТЕРОУУОВНСАМ ІТЕТЕНКЕМНМЯРСІТТЕНІСВЕЬВМІМІ КМУВАКУВІХІАСЕРЕСЬВАННЕІНУВІВАКО ІВООСМНРУКЕІТОКІТВІУВКВООМИВСІЗДВУАЕЧНУСВИРІКНИТОРІЧУРІЬНВУТТУВ МСССІЛТАРХНСУВКВЯКРОБНТНБАРБЕОМТТИМНУВЕОСМОІЕМРІБВКНОЬКТУРІКИОХЕ нЕчаКМакІЖЕНИВВУКЄЕРОМОКНОСКУКРАКОВУХТЕУрКЕНКАРОСТРТКНРМИТНКО во ЕЗАОВІНЕМЕТІУ Fig. and Chad? a person (ЗБОЮ МОЗ) МЕдОоСяСНвАВ 0 АТНУОАЛАВВМСУЕВБОБВАБНКУМСЮОБаИАССрООСНТТВАЄ ССанРЕСОГУУВУСЬКЕХОАКУТРТСРСЕУСНСАТРУ СОНЕТ БРРАСАЛСрЕАВАНАВ АСОрРООРОБУУТРЕОЕАЧеВОЕТЬХИвАКОМОМОТТеМЕВеОТвВУуВНАСМІМРЕОКИКО ШиЕБОНУАНЬВООЇКУВСОЕМНХХВАКСМКЕСКРАНОКЕСНЕТСВОХСМКАСМООсНМОКВО КЕАМУСКОВСМЬОпоостУвоВсВсвНОоВЕсСоЕсСУвУвасУНавсУувРИОСМСЕЕТНК воасикромЕІсавннестНастсЇМАЕРОХ КИТИ ОХ ОВНС БАБНАСТВМЕСАНОС БСНЕУВЗОоКЕСВСеБОонОоЗиТСАБОТОИСАВМРСАвСсЯ Олю Урав ССО; оооАМИСЕаКРСЬМАКБСКМоТОВХ СОСОК ВИ СскОоСаНнОос со УМ зУхасУусевскесянесвоЕнрЕсАееиснВОоВЬсСЕріАЮСЕНСЕСРОЗЕБОРЕЬСВУВУЮСС ЕРБРОВМСАНСУМСВООУУСАСРООКОЗККСЕУКНЕрСЕВОАСКУ ГОБСОовОВареМес ААВСУССЕНСсССоУВаРОСМЕВСТСОВБЕТОТСНЕМТВОСТСОРСВНСОТСТОУОАКВС ЕСРБОМЕОВССТКМРІНЮТЬРОРСВОКОАСУОЬУМНОЕУСАСПОСИКОКТСНаАЕРОСВАХТ ЕМО ТСУОБаОТЕКСАСЕРОНКСВТСАМАКНВВОБРИВСУНОСТСУСВОАБЕВСІСНІМО МЕСЕТСТНМТНОСМРОРСУМООІСТУЮЗУККЕКСЕСАРОКАСЕИСКІНТОБСОВВРОСВУСА тсУрЕГІНСУВСВСеесВАсеВсСОоБУІсСЕСсВВСиВВОТРЕРНОВВИУВОСМВОСВСЬооВНе СБКУЖОСНКРССЬАСОВЕАСОАОСРЬСОВСТЕКАРОСОСЬКРРСВАМНСЕССАЕЕРРЕТРСЇ, РВЯСНЬОММСАВІТІНРИВОНУРОСТТУСАТСВСТВАБІВАТВАТАВОВІТАЛЛСОВАВЕО АБАУЕУАУБЕВРАВОЛЬРОББВЬІОСААНАІУААТІТОВСНВВСОСБАУТЕУКУЮТУТОСОСТ ЧТ ОСА АКТОРА КВВКЕКЕКОВСРКЕЕБАНМОМАРІМВТВМЕТЕВ. РООНКОУБХОСЕНЕТРЕРЕВАВЕАСРОРАСНААУВАВЕВОВО СКОоВКОВІ ВАК ЕТКОРОКЕРСВРАНКАВСЕВКУЮМКАСАВІМЕААХАОКЕ аа миті (ЗБОЮ МОЯ) МААВСИОВОРЕВСІЬУВСУОАТАРМИСТЕЕВрОЇЗАТВМУЮСЕТЬВСВССоСОСКтТТВАС ССОВОЕСОТУУВУСЬКЕХОВКУТРТОРСЗУОУСАТРУТСОМВЕУБРЕРАСААСОВАКАВЕК ЖТСОВОЮРСГТУТВЕОКАКРЕВЕТЬІУКАНОМИМОКТРОВБЬСІВЕВУВНАСМІМНРЕОВИКА СНЕВСНУАНЬВІОХВУВСВЕНУХБАТСМКЕСВЕВМОКЕсНЕторОУОМКАСМОсНМОКЕС КЕАУСКООСМІІВООСТУРСЕСВСВУСЧОСКЕСРЕСУВУРОСУНОВСУЮВИНСОСЕТНИО сІБСОКрІМХСОЗНУРСУМООТСІМНАЕВООТЬСАСРОСУТЗКМНСЕВАВНАСАВИВСАНОЯ ВСНЕУРЕСТВСНОСРВСИБИРТСАБОТОВСАЗМРСАВОСТОУВОЧУЮСКЕСТСРЕОНУСАТС ОБОАМЕСЕСКРСТМАКЕСКМІіІсОУуСоСсьРОВКОІМСОТМІМОСНООСОНОСТСКОВУВ СХУОСУСРЕСКССВНСЕБЕХОКСАБИРСВВОСІСЕОССУОСЕВСВСРЕСЬВСЬНОВУрНОЮС ЕРЕРСІЬМНСАВСУМОЕООУУСАСРЕПТООКНСВУРАРТОРООАСВУТЮССОРЕЛОВКАВОУ АРВСІСОРНОНСУВЬРООМЕВСІСОІВСЕТОТУСНВМІПОСМОСРСВМОСТОТОВУТВЕАС ЕСРВОЧНВОСВЬСОТМРМОСІРОРСЕБВОКСХОСУМОКУПАСрОСНКОКТСНВВВЕКОСОА УТ СБМОСТСУОБОрТЕВСАСРРОМКОВТСТІАКИВЕСУВМРСУМССТСУОВСОБЕВСІСВОСЯ МЕОКТСТЕНТМОСМРЕОРСУМОСІСУ ру МНК АСЕСАВСКАСРОСКІМНІСЕСОББЕСЬХ СА, ТСУ ПЕБІМОУВСВСЕРСКЕСРЕСОБУЧІЕТКРОВЧВКЗМЕКРИСТІВИМЕЮСИВСИСЬОСНКО СВКУЙССКЕРСІДВСОРБОРБАОСРРОООСОБКАЧСОСТОВРСЕКИСЕСТАЖЕРЬРЕЕТР СОРЕАВНІОМИСАВЬТЬВЕККООУРСИТТТТСАТСЕОІВАВРАТНАЛАНОВОГІЛЛСЮКАВ БОАБАУВУАМЕКВРАКОЬРОЕВІСІОБТАНАІМААІТОВИМВВІІТАУТЕУКУЮТУУМИСВ БТШСІИТРУССВУКБУБНОАСУУІСУННТАКВВКЕВЕВЕВБРВОЕВТИКОЗАРЬМРІКНРІ ЕКРООВССЬСТООНКВІБХОСКМЕТВВРЕКАСЕАБВОРАСВОЛОСЕОВЕ ОВЕС ЕВ ЕАЕККІБНКЕТКРРЕСВІЬСЕРАСНАРСРКУПННАУВЕТКОУВНАСКЕ Fig. 2 Послідовність експресованого білка, мішначого лаві ЮБІ-ЕСВК1-4 (мишачого зарі-антигену) авьавОоКЕрЕХОЗМОМУМОВЬОКИНОСОСУКИРОВиКСТВрЕСОТКЕКУКОКВУМЕКУТАВСКС БЕСЗСЕТРУІОСМТЯМОКАБНОМОВМВІЧПВЕВКАНВВХТІЦУБАМОВВМОТІОРОВІТЕКАЄ нЕсмІМШеЕВВОМОТЬКОМТОоТАНКВУОІКстСрОВУОовОосСиКксВеВОиОКтанУАСООМИНКЕС МЕСЧМОгОСМКАХСВОССКРЕНОБСКОЕСЮСВКО У ОМОсЬКСоАСЕВНРОСУНСТСМЕРНОСЬС БТВМОСОССОКОМУСОТНОРСІННСТСВИТОВОКУОССРЕСХЕОРМСКІЛЕНАСЬКОВСНМИ свокЕТаВСсгЕСЕСВРОСЯТСРТСЯТМІОПЕКОГУВвКОВОННнИинНни БЕКОН МО. 5 Fig. BY Послідовність експресованого білка, людського Заві-Ю5І-БОСЕІ-4 (людського І8е1-антигену! ОБЖЬЕЛЕЬЕМОМУМСВІОМОМОСОВЕМРОПЕКСТВОВСОТУРКУСЬКЕУОВВУТВОВРСВЕ ЗВО БЕВОТСООМТЕНОКАВКОМОВИТЧСРЕВЕАНЕВвХТОУВАМОВОКОКУуСРОВІТЕКАВНаСМХ ВЕЗКОКОТІКОМТОУАНКЕУОІВУКСрОУХСКОСМИКЕСЕРЕОПЕВСНУАСОПОВСМКТОМЕСНИ оРБСМВАЇХСКОСсССВЕКНОСВСВоОросВеОохскОоЗУсОКсСІВНРОСУНОУТСНЕРКОСЬСЕ ТНИХ сисркрьМуУсотТнОорСЬМОостТсВМтевОоКкусСсвОвЕСУВОтМСсВІАЛВНАСТВОВСНМКОВСКА У БІШЕЕСЕВСаРОБ1ТОВТСВтМІООо ЗЕ Ю МО 8 Фіг зв Послідовність експресевзного білка, мишачого /882-051-ЕСЕ1-4 (мніНаЧОГО Іде2- антнЕену) СРСБУОХОАТВУ СОВИХ РЕВСААООВАВАВЕВТОЖНОПРОПУУ РОКАМИ ТЬІУКАМ ПВлОМПрЕТРОЕВІЛІВНМОНАСМІМРЕВНМИЕЬНЕВОСНУАНІ ВОТВУВСПЕМУХВАТСМЕЕСКЕ ВчОКЕБНЕ ТОКАР ОММОКЕСКВАУККОСИМОМОВСТУ ОКСАНО ККСОКОСУ рРувосУузавоУуврРИВЮСЬТМИ о сокКррМуСсвиЕнеСсувокСтвВАнВраХхБСАовоСХо кисСЕКАЕНАСАВНРОВНОСПОСОВЕУРОСВВСВОРЕОВМВІРІСА ІЕЕ ООУРКОВОсНИННИВ ІЗ МО. т З Fig. ЗЄС Послідевність експресованого білка, людського Лав23-П5БІ-ЕСР1-4 (людського І8е2-антигену! АВЕМОУКЕМОБВАЦБКВУМСВЬОВОАССрОректУВАСОСОНОВСВКУу сьо ОВ СЕХСНОАТРТУССНВЕУБЕАЄВАСВВАНАНАЯВССРОПРСІУУІРРОКАИРНВЕ КО УВА ВМО ТТРЕЕЕБОХЕКУВААИМІМиБОВКЕБОНЕВОВУАНЬЕСО ТА ВСОЕВХУВАХСИКРОСКвЕКВ пВРЕсСНУТСООХОМКАСМООММОКВОКЕАУСКОССМЬСКОпСТтУвОовоВоВОНОВЕСОЕСУВУ РОСУНОБСУЕРНКОСВСЕВТММСОІОСОКОСУСОБЕНРОТНСОТСІВАВРООХВСТСРОСУ ВОВКИ СЕКАБНАСТЕМЕСАМОСОСНЕУРВОКВСНСРОСНЕСЕТСАТОтОЕКЕОЬьУКВОБаНннИиНИия (ЗЕСЮ МО. 8) к - Fig. 30 Coffee: 2 3 55 5 7 8 813 M О1203 Mi 029300 MOM OM 2228 253935 32 3335 35 ZK 31 3833 In Further, the zhyn ia SO is NOT iSpochna - SOKNTI zkayumosbo bo in ot E both: here is kt BI KIN U vo a zva moga S -y vo b B U 5 5 5 5 6 x 5 Uh b 3 5 5 8 p XA 83 B 7? hi he xx a zvayumoga V Kk hu a 5 U V 55 56555658 BA 585: AZ3I5 hu ha znayuho:a? 04 ko t 4 5 y 885 25 Kk x 0 t s, 55 l A 5 2 A A 85 W t R W U ХВ У ХА zkayumogo A HU ov :ho 56555855: 35357 REKHIBIVEVU zvashkogt? 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Spoina-SOKIZ OSalast contact SIK 13 S zh BEATUTsSsO058U 9810 hu. 96 S-i EE Z RA t her si0 057 185 RB TE ost xx 5 V I XX ZEOYUMO: 97 V EVEATITSO9IU55b TE Z 008 XX M EE I ZHK 5BEOIYUMO.: 95 0-4 EE V rAItsSI00t555RITIR ob 9 v IC 5ZEOSHMO: 99 A BO E AT I SI 05 RR TIV o a 07 xx EE I X 9BOIYUMO.: 10 AL BO EBEAET TT СсСИ0ОО0тх tA TE Об тх 5 B I ХХ ZEOIYUMO 18 A-2 BE VEATITSO95U 788 TE Zb t KK 7 B I: XX B5E0IYUMO. 56 V EV EE AT U U Si 0 5 t 788 TIC o 007 U EI Kk FAILURE MO 100 V EE 2 KE AT ис10057 75581007 KU B 1 Ж 5EOSHYUMO. LO V- B OZ EV HERE si0 0558 TE ab tk IN EE AND ZK 5BEOIIUMO; 102 BAZ Z OO BATUTI 5 JOKES opt t 1 xx B5BEOIYUMO: 103 0-2 EV EATU IN сИОО0т8 5585 ТИК 506 ху жк I ХХ B5EOIYUMO: 104 OZ 5 o Bat5s100uU8 558 ТИК 9 5 1 xx ЖЕЙЙУMO. 105 p-4 OO EATUTSI0O00t555 8: TE 007 HU EE I XX ZEOYUMO. 1065 0-5 EORATTTSI007555R8RB To 5 U B 1 XX ZEOIIUMO 107 Fig. 485-2 Sequences of NUV-NI Nomerza Kabat (kaae BO IR antibodies 00861271 55555151 TE A, v-1, Ag, ! 35 and A-TiSh101 se EI titid xx ' chIvbihi no and also 11.19.5771 ! Sequences NUK-NO tya rr Y "chit t| RI visisi1x t oh aAiviv Mix y A-IVISYKI i i i i ! (also 12, 20) Fig. ON THE SEQUENCE OF NUK-NI cones in BIK B antibodies with ris Okh 101102 aged in ZK A ho Fig. ZV Consistency NUV-KI I Rooms Kabatom | NEO OtO MO ! pp rt thread prp tyt there at tutu ru pek kino Me antibodies IIA 25 vim M a p p V i v. A-no, Ai, and N N and N and ! ! ZE and their rA rya fa ro U Zh Zh Ya t Id: y and veiivmit AT oo) bakozhechya 23.30) Sequence: NUVK-O Nomerza Kabatom duv s antibodies ZO | Be ba | BI 56 and, ki, B-2 I | And | : well I A V IRE Eh |i d-i-VisIt : | | io (also 15, 2331 Pa VKA ZK PANNA; ZK ZK KAK, DAK Sequence. NUV-1 Z Number Kabat, zZEboTa Mo inn o; now pet mon me mo chany men dv "shruchnnnnshsh cheny y, I her I TU eh and Ky | M i M m r | X 1i1b'also' 32) khonsanymMmo M | m NYA m MEN R/A ! vyt | t more Codes pgt tt tt o ss s 2 2 2 2 2 o 2 2 2 2 2 2 o 2 " po o o o o o o o o M 2 2 2 2 5 2 2 2 2 2 2 2 o o o o o o o o p o tt tt o Fig. 6 Sequences of the framework regions of the variable lomen of the light chain of antibodies A. A-11 4-2 WHAT-ENVI sAvr be biv Mei tn biv be Ro Zag Magi vu Zet Aa Bag Mvi Oij Ar Aga uv Tvg Pe Tu was? (8EO Y MOZ) SHOV Tur tuye bip Sip uv Rto Su Guz Av Rez uv io em This Tut? (5BO YUO MO:44) THIS Zb in Ro Zeg Ago vo Zeg Su Zeg Su Zvg SNU Te Avr Re Tng I vu TNe Ve Zeg Zag em iy Ro Z Avr Re Div Ti Tug TugSuvbya (BEO Yu MO:45) iszhshchya buresiu biv Su TAgi uz ma Or Me uv AeiOYA (560 Y MY) Sequences of the framework regions of the variable domain of the heavy chain antntil A. A-1 I A-Z NEW So Ua ti web varsv beg Su (mu Si and en mag iv Rgo Svu (MU Zhegiets Agoi you Bag Sub Av Aa be? (I FAILED MO) NOENa Zbgrr ma Aga iy deya Ro Su Buv Ou Ben iv Ttr uv Su (BO OO MOHAV) no bat Rne ih Tse beh div Ar Tr Begi uv Ap TAg AV tugi er Si Meii Avo Begi vu Ag Aa BE Avr Tk Ada Mvi Tut Tug was Mal (5EO Yu MO:49) NOVA ter Ou iv lu Tvei vm Uvi Tk Mag Zagbe!? 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NU V OO KA A i PO ni i ; she ИЙ 4 ! -0 и ! now nn at 5 and 15 o'clock Two Fig. 115-1 Isotny control antibody Anti-)ats 0 5 10 15 Ko) o ZT. Z A TL 8 X A «-«A«Sh-E « A «A « YUK « A I 5 AS E S --- - - - - « - - « «« 204 t! ! | I E and and ! and | ! 10 Ind i a ii » I-so! 4 d y ryy I nyk I OA Anyu SHY NN san A V shu Y not de a ; | r A: And - ! a r v a A SCHE SCHO da v i z V u V SCHE rhyme: BUT DY SHY ss "Y SCHO brani roti from roti | | Or SHE and | : and I -e sh | ! | ! 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NN ; I toutindividual volume of the tumor WE NOT ; slyayu- Individual development yes NO ZINNA MNNNI ZANE M MNE --- shi shanya zlyanya INDIVIHO) what and t N y! t m, 15 the end of the study and Y; 5 I ; and decoys MM E is the fitted curve of Ayaovrite «y | and, ! 1000 men The applied approximate Gr i o. control curve (carrier) Kk U | I /k s; Y M o initial volume of the tumor and r ly zhi VV Bod r Shrik: aa He ek teo VKeNY z tdnny uschn DY st v Kit, 010 20 3040 0 60 Day Fig. 128 in Antimlo A Ag A a no a i s Z PO v o o ON v S EKO VO a OK o o. LE is about Pe in o s "-Intakite MAT : S. PU v V i p NI ON I her NN v V M ONY pp skinnofrnnen VS KO PEKY OKKO KOH KN KK yan M KiVI. frzgmen NS N : XX MON F W KN XX MONO Fig. 13A "SAME compression (4,016-4,793.min, 25 scans) frementania 250.0 V VSROE K 042413y Expanded bzotopne shi i hny razshnrsnykh 12.01 : | ! : : | and : : N N N i 1 N N N i V we i | and ! : : ! 14982532! 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